Neurobio of addiction final

DSM-5 definition of substance use disorder

"The essential feature of a substance use disorder is a cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues using the substance despite significant substance-related problems."

different types of responses to drugs

"full" agonist Partial agonist competitive antagonist inverse agonist

haplotype

"haploid genotype" - a specific combination of two or more DNA marker alleles situated close together

Face validity

"on its face" does the animal model appear to model the human condition?

Log-Dose Response curve

% maximal response vs Log concentration - take long of concentration so that EC50 is easier to determine from the curve

quantitative trait

(complex trait) the existence of a range of phenotypes for a specific character, differing by degree rather than by distinct qualitative differences

Empathogen-Entactogen

- "empathogen" denotes chemical agents inducing feelings of empathy. - Major drugs in this class are MDMA, MDA, MDEA and most are phenethylamines

Effects of the GABAA receptor antagonist IPPO on responding for ethanol or water

- # responses in non-preferring, wistar or preferring rats in groups that have been administered baseline, 0, 5, 10, or 20 micrograms/kg of IPPO. - Experiment also repeated for water instead of alcohol. - Concentration of IPPO reduces responses for ethanol but not water (except for at highest dose of ippo in preferring rats). This shows alcohol self-administration is sensitive to reducing GABAergic function.

Are GABAA receptors the only putative target of alcohol action in brain?

- % inhibition of current vs ethanol concentration for NMDA, kainate, and quisqualate (ampa) receptors - Ethanol inhibits glutamate receptor function, with NMDA responses much more sensitive than kainate or AMPA.

Spontaneous Nicotine Withdrawal

- % of baseline ICSS threshold vs hours post pump removal - increase in ICSS threshold -also increase in overall somatic symptoms of withdrawal

Influence of withdrawal on ICSS threshold

- % of baseline threshold vs hours post ethanol in ethanol and control groups. - As the alcohol clears the body (withdrawal) ICSS threshold is elevated, indicating a negative reward state.

Effect of 6-OHDA lesions of the nAcc on cocaine self-administration in rats

- % pre-lesion cocaine intake vs days post lesion - in control rats, Pargyline rats (Enhances effect of 6-OHDA, is an MAO-B inhibitor) , and pargyline + desmethylimipramine (NE reuptake inhibitor, spares NE neurons). - both decreased cocaine intake in rats compared to control

6-OH DA lesions of DA terminals in nAcc

- 6-OH DA lesions of DA terminals in nAcc cause extinction of nicotine self-administration - number of infusions vs week and day for sham and lesion rats - lower number of infusions in lesion rats

How does being alone/ interacting with others affect how stoned people get?

- A greater percentage of users get less stoned when they want to interact with others - A smaller percentage of want to get more stoned when they are by themselves

Pharmacodynamic (functional) Tolerance

- A spectrum of adaptive changes that occur in the brain or spinal cord to offset the effects of drugs, in an attempt to restore homeostasis. - The end result is production of a more normal state in the continued presence of the drug. - Such adaptive changes have been found in the levels of neurotransmitters, the affinities and numbers of neurotransmitter receptors, and the up- or down-regulation of the expression patterns of a wide variety of genes. - Tolerance can develop to the locomotor stimulating effects of cocaine and can develop to more than one aspect of a drugs actions

Imaging of craving in medication testing

- A taste of alcohol and a series of alcohol-related pictures, neutral beverage pictures, and visual control images were provided to volunteers after 7 days of double-blind randomly assigned daily dosing with 50 mg of naltrexone, 0.50 mg of ondansetron hydrochloride, the combination of the 2 medications, or matching placebos. - both naltrexone and ondansetron reduce alcohol-stimulated dopamine output in the ventral striatum, the current study found evidence that these medications, alone or in combination, could decrease alcohol cue-induced activation of the ventral striatum, consistent with their putative treatment efficacy. - graphed craving vs (alcohol - beverage brain activation) for social, NalOnd, Nal, Ond, and placebo - Strong curvolinear relationship across groups between the mean craving for alcohol during the scanning session and the mean of the alcohol minus beverage comparison in the ventral striatum

genes/alleles influencing alcohol metabolism

- ADH1B/ADH1C increase activity of alcohol dehydrogenase - ALDH2*2 decreases activity in alcohol dehydrogenase - both cause aversive buildup of acetaldehyde

Mechanism of Action of amphetamines

- Act presynaptically to inhibit DAT and reverse transport DA from cytoplasm. - When amphetamines enter synaptic vesicles via VMAT2 that causes collapse of vesicular pH gradient leading to DA release into cytoplasm. - High efficacy agonist at intracellular trace amine-associated receptor (TAAR1), a Gs/Gq GPCR - Inhibits excitatory amino acid transporter 3 (a glutamate transporter) - Inhibits monoamine oxidases at high concentrations - Low potency agonist at 5-HT1A receptors

Nicotine reinforcement

- Activation of α7 receptors on glutamate terminals in VTA produces LTP of excitatory transmission and increases glutamate release onto VTA DA neurons. - Activation of α4β2 receptors on VTA DA neurons - More rapid desensitization of α4β2 receptors on VTA GABA neurons (which inhibit the DA neurons). - Similar effects on serotonergic neurons of dorsal raphe may contribute to antidepressant actions of nicotine.

MDMA mechanism of action

- Acts as a SERT, NET and DAT (less) inhibitor, as well as enhancing neurotransmitter release. - Agonist at 5HT2A/B/C and 5HT1A receptors as well as D1/D2, several adrenergic and muscarinic receptors - Seems to be a combination of fluoxetine (Prozac), amphetamine and LSD effects.

Factors influencing psychostimulant action: corticosteroids

- Adrenalectomy blunts cocaine self-administration - corticosterone facilitates DAergic response to cocaine and its reinforcing effects - number of self infusions vs dose of cocaine in control vs adrenalectomized rats, control had greater number of infusions - % Da increase in NAcc vs time in LR and HR rats when given corticosterone- greater increase in HR rats

Preoccupation and anticipation of cocaine

- After withdrawal from chronic cocaine intake, a single cocaine challenge dose may induce relapse to drug taking (or paranoia) through increased DA release associated with and dependent on increased glutamatergic release, which may be a consequence of interoceptive cues associated with drug taking. - In absence of drug taking, environmental cues nay induce craving and relapse through enhanced glutamatergic transmission with little contribution of dopamine.

Acute reinforcing effects of alcohol

- Alcohol could inhibit GABAergic interneuron terminals in VTA, leading to disinhibition of DA cells. - It may similarly inhibit glutamatergic terminals innervating NAc neurons. - It could also inhibit NMDA receptors on NAc cells.Lastly, ethanol may activate endogenous opioid pathways. - These cells then inhibit GABAergic interneurons in VTA.

What is the gateway hypothesis? How is it showcased visually?

- Alcohol ➛ tobacco ➛ cannabis ➛ other illicit drugs - There is rapid rapid progression from first use to continual use of alcohol, tobacco, and cannabis and over time the harsher drugs begin to coincide with these curves, making people more likely to partake in opiods or hallucinogens once they have began using the first three drugs

Why are single-cell transcriptomic approaches important to the alcohol field?

- Alcoholism is a complex disease - Alcohol is involved in over 200 pathologies and health conditions-multiple effects in brain: mechanisms are region and cell-type specific - Understand how alcohol affects the brain at the cellular and molecular level - Hypothesis: Cell type-specific gene expression patterns associated with alcoholism will unmask important mechanisms of alcohol action missed by bulk analysis

Molecular sites for alcohol and their consequences

- Alcohols/Anesthetics bind in partially hydrated protein cavities - Site must be critical for protein function - very small free energy changes, very small volume changes - Emerging evidence links different protein targets with different behavioral actions of alcohols/anesthetics. - GABAA receptors appear important for alcohol ataxia, motor stimulation and aversive effects. - Alcohol also inhibits NMDA receptor function. actions are enhancement of inhibition (GABA, glycine) and inhibition of excitation (glutamate)

Pharmacokinetics: influence of pH on amphetamine absorption

- Alkalinizing urine pH extends t½ because molecules are uncharged, allowing for renal reabsorption - Acidicifying urine pH shortens t½ because molecules are charged, preventing reabsorption

Nicotine replacement therapy (NRT)

- All methods of administration ~ equally effective (increase quitting by 50-70%) - Combining patch with more acute form may be more effective (prevent protracted withdrawal and episodic craving) - Counseling increases effectiveness• Can be tapered over 18-20 weeks

Mechanism of action for PCP

- Allosteric modulator of NMDA receptors - Also has inhibitory effects at nAChRs - Potent D2 DA receptor partial agonist - noncompetitive antagonist at the NMDA receptor - PCP does not not antagonize AMPA/kainate effects

effects of micro dosing psychedelics

- Analyses of daily ratings revealed a general increase in reported psychological functioning across all measures on dosing days but limited evidence of residual effects on following days. - chronic, intermittent, low doses of DMT in rats produced an antidepressant-like phenotype and enhanced fear extinction learning without impacting working memory or social interaction.

drug

- Any substance that is used "to bring about a change in some existing process or state, be it psychological, physiological, or biochemical" - do not do new things, modify what is already there

Positive reinforcing effects of stimuli associated with drug self-administration: conditioned reinforcement paradigm.

- Approach allows investigators to characterize incentive value imparted on neutral environmental stimuli after paired with drug self-administration. - Subjects trained in an operant chamber with two levers (one active providing drug, one inactive). - Responses on the active lever lead to presentation of a brief stimulus (eg., a sound) followed by drug injection. - The ability of the drug-paired stimulus to maintain responding even in the absence of drug delivery provides a test of the conditioned incentive effects of drugs. - Also provides animal model of craving since the incentive motivational effects of the stimulus are tested in the absence of drug administration.

binding of benzos and barbs to GABAa receptor

- BZ and Barbs act at different sites on GABAa and at a different site than GABA - Evidence for unique sites: no direct action alone, do not inhibit GABA binding, and do not affect GABA release - benzo binding site is between a1/gamma2 subunits? -investigated by taking cells from South African clawed frog, inject RNA, and measure Cl current through receptor -BZ and Barbs potentiate Cl- influx produced by GABA (Ex. when measuring current of gaba receptors when different concentrations of just gaba is applied and when gabba and diazepam are applied, EC50 is decreased and max efficacy is not changed)

Vaccines against drugs of abuse

- Basic concept: sequester drug in blood, preventing it from acting in brain. - First generation conjugate vaccines against nicotine and cocaine failed in clinical trials but second generation vaccines provide greater promise - Drugs too small to be recognized as foreign by the immune system - The drug on its own is referred to as a hapten but when combined with a larger molecule the complex becomes an antigen. - often use a molecule to link a drug to a carrier protein that is then recognized by antibodies - Approach works better with more complex drug molecules (eg. opioid vs ethanol).

neurobiology of binge/intoxication stage

- Binge/intoxication stage heavily involves the basal ganglia. - Roles of basal ganglia: voluntary motor control, procedural learning of routine tasks/behaviors, action selection. - Ventral striatum (NAc, olfactory tubercle and VP) - involved in motivation and reward. It is the major integrative center for converting motivation into action - Basal ganglia receive afferents from prefrontal cortex and midbrain dopamine system. - Basal ganglia projection is from the GP to the thalamus. These motor and sensory signals are in turn relayed to the cerebral cortex. - Basal ganglia function as a set of cortical-striatal-pallidal-thalamic-cortical loops that encode habits related to compulsive behavior.

Compare and contrast CB1 and CB2 receptors

- CB1 receptors are most abundant Gpcrs in the brain - CB2 are mainly peripheral but some small amounts in brain including VTA dopamine neurons - Most Gi/o coupled (inhibitory)

Describe the locations of CB1 and CB2 receptors with respect to the dopamine pathway between the VTA and nucleus accumbens as well as the influence THC has on the activity of this pathway

- CB1 receptors located on the GABA and glutamate cell inputs to dopamine neuron - CB2 receptors located on dopamine neurons - THC reduces GABA inhibitory activity, which increases dopamine activity and contributes to rewarding effects of THC - TCH reduces excitatory Glutamate input, which decreases activity in the domaine neuron and contributes to aversive effects of THC - Inhibition of dopamine neurons at CB2 receptors contributes to aversive effects of TCH

What does epidiolex do?

- CBD solution used for treatment of seizures associated with tuberous sclerosis complex in patients one year or older - Also used for treatment of seizures in LGS and DS

CHRNA5 and Risk for Tobacco Addiction

- CHRNA5 polymorphism in humans associated with increased risk of nicotine dependence. - Blockade of alpha 5 containing receptors reduces withdrawal signs in rodents. - Chrna5 knockout mice self administer more nicotine than wild type mice. - alpha 5 habenula-interpeduncular pathway mediates aversive effects of nicotine.

Nicotinic acetylcholine receptors (nAChRs)

- Cationic cys-loop LGICs, conducting Na+, K+ and (in some cases) Ca2+ ions. - Widely expressed in CNS. - Found pre- and post-synaptically.Na+ entry causes depolarization, leading to opening of voltage-dependent Na+ channels. - Presynaptic calcium influx increases neurotransmitter release. - Postsynaptic calcium influx activates many cellular processes (eg. CaMKII)

Proposed mechanism for alcoholic liver disease

- Chronic alcohol abuse increases gut permeability resulting in high circulating endotoxin that reaches the liver via portal circulation. Endotoxin (LPS) recognized by the Toll-like receptor (TLR)-4 complex on resident macrophages or Kupffer cells in the liver, leading to production of proinflammatory cytokines, particularly tumor necrosis factor (TNF)-α, and resulting in injury to liver cells (hepatocytes). - alcohol-induced changes in tight junctions cause increased intestinal leaks that lead to translocation of bacteria-derived products such as LPS - molecules enter the circulation to the liver where they activate endothelial and stellate cells as well as hepatocytes, resulting in a chronic inflammatory environment aggravating organ injury. - Mechanisms for inflammatory and neuroimmune actions of ethanol include leakage of endotoxins from gut, liver inflammation releasing cytokines that reach the brain and direct actions on immune signaling in brain.

Describe the chronic actions of opioids at their receptors

- Chronic exposure to opioids leads to opioid receptors being phosphorylated by GPCR kinases (GRKs), which then leads to β-arrestin binding, and this causes opioid receptor desensitization and receptor internalization via clathrin-dependent pathways - Opioid receptors being phosphorylated by kinases - Opioid receptor desensitization and internalization Recycled or taken to lysosome - drop in adenylyl cyclase activity leads to lower camp levels and lower PKA levels. Chronic use leads to gradual increase in both of these levels but during withdrawal, compensation leads to great spike in camp levels and gradual decrease in adenylyl cyclase activity - CAMP response element binding protein (CREB) is a transcription factor binding to CREs, that can increase or decrease transcription of many genes, such as c-fos, BNDF, enkephalin, PER. - DfosB is a transcription factor that acts in accumbens as a "sustained molecular switch" in the development of addiction, triggering a series of transcription events that foster compulsive drug seeking. This lasts for months after drug withdrawal due to the long half-life of DfosB. DfosB expression levels could be used as an addiction biomarker. - both increased by drug exposure, with creb increaseing more quickly but delta fos b decreases more slowly

Behavioral therapy

- Cognitive-behavioral therapy -recognize negative thinking, enhance coping - Motivational interviewing - remove ambivalence, set goals - Contingency management - incentives - Community reinforcement - peer support - Family behavioral therapy - social support, repair relationships Evidence: - Volitional social interaction prevents drug addiction in rat models - trained rat to do response to free friend from chamber, and taught to lever press for drugs - given choice between social interaction and drugs (?)

Steatosis (Fatty Liver)

- Common - Not necessarily due to alcohol (NAFLD): also due to obesity, high blood sugar (type 2 diabetes) or triglycerides - Transient and reversible - Few symptoms - Hepatomegaly - Slightly elevated liver enzymes

Meyer-Overton correlation

- Correlation of anesthetic potency with lipophilicity - graph of potency vs oil/water partition coefficient - greater oil/water partition coefficient is correlated with greater potency -points toward theory of inhalants and general anesthetics acting through cell membrane

DA and CRF levels in amygdala during precipitated nicotine withdrawal

- DA deficit and CRF increase in amygdala with precipitated nicotine withdrawal - Desensitization of α4β2 receptors on VTA DA neurons reduces their activity. - Downregulated opioid signaling contributes to somatic signs. - Downregulated activity of serotonin neurons in median raphe may contribute to anxiety and depression in nicotine withdrawal. - CRFR1 antagonists reduces nicotine self-administration during acute abstinence.

Effects of alcohol self-administration, in nondependent, ethanol-naive, and dependent rats during ethanol withdrawal, on DA efflux in the nucleus accumbens.

- DA dialysate neurotransmitter levels vs time in dependent, non dependent, and ethanol-naive rats. - In dependent rats, DA levels fell during withdrawal and were restored to pre-withdrawal values during self administration - In non dependent rats, DA levels remained the same during withdrawal and rose above baseline during ethanol self administration

LSD type hallucinogens

- DMT (Dimethyltryptamine): naturally-occuring LSD-like substance in plants; e.g. Psychotria viridis - Morning Glory Seeds: lysergic acid amide (LSA) - Bufotenin (5-hydroxy-DMT) - Psilocybin and Psilocin (magic mushrooms) - Psilocybin is a pro-drug - 100 times less potent than LSD - Ayahuasca - Made by brewing Psychotria viridis shrub (contains DMT) with the Banisteriopsis caapi vine (contains MAOIs) - The MAOIs allow DMT to be orally active - Mescaline - Isolated from peyote cactus (Lophophora williamsii)

What is one way the alcohol and cannabis impair cognition?

- Decrease word recall ability with increase in amount of alcohol or THC administered - Number of correct responses as a function of list presentation order and amount of THC and alcohol during their 1st, 2nd, and 3rd list presentation

Describe depolarization induced suppression of inhibition and how cannabinoids are related to this phenomenon

- Depolarization of a postsynaptic cell causes the release of cannabinoids that bind to receptors on presynaptic cell and inhibit the presynaptic inhibitory cell - could also inhibit presynaptic excitatory transmission

Steroids and dopamine

- Dopamine (DA) released into n. acc. from neurons in VTA during natural rewards (food, sex) and by drugs that are reinforcing. - Testosterone injected into n. acc. produces place preference but there are few steroid receptors in n. acc. - CPP induced by systemic testosterone blocked by D1 and D2 receptor antagonists.

neurological mechanism of action of psychostimulants

- Dopamine increase is essential, but not proportional to the "addictive potential" of the drug - two major DA systems - Mesocorticolimbic (motivation, exploratory activity): DA projections - Nigrostriatal (Motor, stereotypies): DA projection from SNc to striatum from VTA to NAc and PFC, Glu projections from PFC to VTA and NAc, and GABA from NAc to VTA.

experiment investigating the effect of muscimol ( in dependent rats

- Dose Muscimol vs number of reinforcers - Rats were trained to lever press for 10% ethanol. EtOH-dependent (2 weeks vapor exposure) animals responded more for EtOH than did air control nondependent rats. - muscimol is gaba receptor agonist - Intra-amygdala muscimol significantly decreased responding for EtOH in EtOH-dependent rats, but had no effect in nondependent controls (had activated gaba receptors so did not have craving) -These data suggest that the reinforcing effects of EtOH and neurotransmitter pathways mediating reward are altered after the development of dependence.

Describe the development of opioid tolerance

- Dose-response curves to morphine in different tests - There is tolerance to analgesia, hypothermia, but less tolerance to lethality - Letahality graph for acute tolerance is similar to the standard whereas for analgesia and hypothermia it is left skewed to show a greater tolerance. - in addition, sensitization to locomotor effects

What are three medical uses of cannabinoids that are approved?

- Dronabinol (pure isomer of THC): approved for nausea and vomitting in chemo patients, anorexia, and AIDS - Nabilone (synthetic): same therapies as above - Nabiximols (mouth spray): treats multiple sclerosis ** all have pharmacokinetic disadvantages due to oral administration

Animal models of craving

- Drug seeking induced by the drug or stimuli previously paired with drug taking (reward craving) - Drug seeking in response to an acute stressor (relief craving)

BZ site inverse agonists

- Drugs that have the opposite effects of agonists, requires some receptor activity. - measured % max current vs gaba concentration for GABA + Diazepam, Gaba alone, and Gaba + DMCM (inverse agonist). - The GABA concentration-effect curve is leftward-shifted by agonist and rightward-shifted by an inverse agonist. - measured % max gaba current vs benzodiazepine site ligand concentration using high efficacy benzo site agonist (diazepam), partial agonist (bretazenil), inverse agonist (DMCM), or antagonist (flumazenil, Ro 15-1788) in the presence of a fixed, EC20-equivalent concentration of GABA. - Agonist increased current while inverse agonist reduced it.

Orexin receptor antagonist

- Dual orexin receptor antagonists (DORAs) are a new prescription sleep aid for the treatment of insomnia. - DORAs block both OX1 and OX2 receptors by competing with orexin A and B - Orexins A and B are secreted by neurons in lateral hypothalamus projecting widely in brain and spinal cord. Necessary for wakefulness (narcolepsy with lose of these neurons) - Suvorexant and Lemborexant are DORAs prescribed for treatment of insomnia. Decrease sleep latency and help with sleep maintenance. (some very small abuse potential)

cocaine Negative affective state mechanism

- Dynorphin provides negative feedback via k receptor activation on DA cell terminals. - Chronic cocaine/opioid exposure upregulates this negative feedback via CREB. - Elevated CREB in nAcc produces dysphoria that is seen in withdrawal.

Experiment regarding efficacy of Baclofen on AUD

- Effect of the GABAB receptor agonist baclofen on the alcohol deprivation effect in Sardinian alcohol-preferring (sP) rats. - Alcohol consumption was measured for 1 hr after 7 days of abstinence. - Baclofen was injected i.p. 30 min before introduction of 10% ethanol. - measured alcohol intake vs baclofen concentration in alcohol deprived rats and alcohol non deprived rats. - greater baclofen concentration decreases alcohol intake - however, not effective in meta analysis of human studies and not FDA approved treatment

Describe the experiment which investigated the relationship between opioid receptors and the reinforcing properties of TCH? What were the results?

- Effects of naltrexone on Self administration response to THC and cocaine over multiple sessions. Naloxone decreased responding for THC but not for cocaine - also investigated Effect of intra- venous Δ9-THC, WIN 55,212-2 (higher efficacy cannabinoid), and heroin on dialysate dopamine in the shell (upper panels) and core (lower panels) of the nucleus accumbens - measured dopamine output in shell and core of NAcc as a percent of baseline vs time after drug administration in patients given Δ9-THC, WIN 55,212-2, and heroin in patients that were also administered naloxone (opioid receptor antagonist), rimonibant (SR141716A), or saline - dopamine increase due to THC or WIN can be blocked by both rimonibant and naloxone

effects of ethanol on dopamine concentration in nucleus accumbens

- Effects of oral ethanol self-administration on dopamine release in the nucleus accumbens in Wistar and alcohol-preferring rats in control vs ethanol rats. Ethanol increased dopamine concentration to a greater extent in P rats - Dopamine release in the nucleus accumbens of Wistar and P rats responding for saccharin reinforcement in control vs saccharin groups. No difference seen between control and saccharin in P or Wister rats - demonstrates that dopamine release responded to ethanol only, and not other reinforcing compounds.

ICSS

- Electrical stimulation of certain brain regions is rewarding in both animals and humans. - Rapid learning of behaviors rewarded by ICSS - Animal works to directly stimulate presumed reinforcement circuits in brain. - Drugs of abuse decrease ICSS thresholds (correlation between ability of drugs to decrease ICSS thresholds and abuse liability) - Aversive stimuli increase ICSS thresholds

Linking Benzo Receptor Subunits to Specific Behavioral Actions of Diazepam

- Endogenous gene can be replaced with a mutated but active gene (Knockin mouse) allowing subtle and selective modification of protein function - Mutation of single amino acid in GABAA receptor a subunits prevents action of diazepam without altering action of GABA. -Production of mice with mutant subunits provides powerful test of the importance of subunit for actions of diazepam. -Removal of diazepam action in receptors containing alpha1 subunits prevents diazepam-induced decreases in motor activity and memory, and partially reduce anti-convulsant effects. - anxiolytic-like, myorelaxant, motor-impairing (ataxia) and ethanol-potentiating effects of diazepam were fully retained in alpha 1 mutant mice. - alpha2 and alpha3 rendered insensitive to diazepam. anxiolytic action of diazepam absent in alpha 2 mutated mice and present in alpha 3 mutated mice as seen in elevated plus maze test. Additional role for alpha 2 containing gaba a receptors in preventing PTZ and MES induced seizures

Animal Models of Relapse : Conditioned Reinforcing Effects of Drugs

- Environmental stimuli play a role in drug taking behavior since environmental cues repeatedly paired with primary reinforcers will acquire incentive properties (classical conditioning) - Conditioned reinforcing effects contribute to drug craving and therefore can play a role in relapse. - Presentation of stimuli previously associated with drug delivery increase relapse rates and self-reports of drug craving in humans - These cues include sights, people, smells and situations associated with drug use, which become predictors of the onset of drug effects. - stimuli begin producing changes in organ systems before the drug is administered - demonstrated by giving the user a placebo when drug was anticipated. - Environmental cues previously associated with drug use produce physiological changes that users interpret as drug craving or withdrawal.

patterns of smoking

- Escalation among regular smokers. - Erratic pattern in converted chippers but several quit. - Chippers can sustain low but constant use (~1-5 cigarettes per day), social smokers - Chippers report no withdrawal signs if they don't smoke

effect of ethanol on dopamine and endorphins

- Ethanol increases extracellular dopamine in nucleus accumbens - Carfentanil displaced by endogenous opioids in nucleus accumbens during ethanol challenge

relationship of alcohol to punished/unpunished behavior

- Ethanol reduces suppression of of behaviors induced by punishment while decreasing unpunished behavior - Ethanol increases conflict (punished) responding at doses that decrease unpunished responding (same animal for both behaviors) - responding for ethanol vs dose of ethanol in conflict and random interval groups - responding increases with dose in conflict group and decreases in random interval group - Relative potency for reducing anxiety in humans is correlated with potency for increasing punished responding in rats for drugs of different chemical structures.

Extinction with and without cues associated with IV drug self-administration.

- Extinction provides a measure of motivational effects of drugs by assessing persistence of drug seeking behavior in absence of response-contingent drug delivery. - Subjects trained to self-administer a drug to the point a stable baseline of responding is achieved. - Extinction occurs by no longer rewarding responding with drug administration. - Measure duration of extinction responding and the number of responses made during the entire extinction session. - Can also study the probability of reinstating responding under extinction conditions using previously drug-paired stimuli.

Fetal Alcohol Spectrum Disorders

- Fetal alcohol syndrome - Partial FAS (pFAS): does not meet full diagnostic criteria for FAS but has some facial abnormalities and growth retardation - Alcohol-related Neurodevelopmental Disorder (ARND): intellectual disabilities, behavioral problems, poor impulse control -Alcohol-related Birth defects (ARBD): congenital malformations/dysplasias in cardiac, skeletal, renal... systems

Conditioned context-specific tolerance develops to the ataxic effects of alcohol.

- Following baseline testing, the tilting plane apparatus was moved into a novel laboratory room rich with distal cues. - During a 7-day tolerance acquisition period, subjects in all groups were given two injections per day. - The first injection took place in the room containing the tilting plane apparatus. Immediately following this injection, subjects were placed inside of the apparatus. - No slip angle measurements were taken during the tolerance acquisition period. - The paired group was administered alcohol injections in the testing room and saline injections in the colony room. - The unpaired group received saline injections in the testing room and alcohol in the colony room. - The control group received saline injections in both. - Previous experience with alcohol in testing room diminished effects of alcohol on performance.

Smoked marijuana vs oral thc effects on heart rate over time

- For people who smoked, great increase in heart rate at beginning that begins to decrease - For oral administration, increase in heart rate a little bit later that begins to decrease at around 240 minutes

biased signaling

- G-protein-biased compounds produce antinociception with reduced side effects. Fentanyl is a clinically used opioid analgesic that preferentially recruits β-arrestin downstream of the μ-opioid receptor, triggering a second wave of G protein-independent signaling. Consequently, fentanyl produces significant respiratory depression. b-arrestin KO mice said to be less sensitive to respiratory depression - in contrast SR-17018 is an opioid that preferentially engages G-protein signaling, producing antinociception with minimal respiratory depression relative to fentanyl.

Genome Wide Association Studies (GWAS)

- GWAS: a research approach used to identify genomic variants that are statistically associated with a risk for a disease or a particular trait. - Obtain DNA from people with disease or trait of interest (cases) and unaffected controls - Run each DNA sample on a SNP chip to measure genotypes at 300,000-1,000,000 SNPs in cases and control - Identify SNPs where one allele is significantly more common in cases than controls -The SNP is associated with disease or trait of interest - cannot on their own specify which genes are causal

Gene Coexpression Networks

- Genes that are differentially expressed between these rat lines could be important for mediating any differences between the rat lines. - The main difference between the lines is alcohol preference, but it is not the only difference between the rat lines. - Differentially expressed genes (DEGs) could underlie differences we do not care about. - Gene co-expression network analysis partitions the variability in the gene expression dataset into groups of genes that are similarly expressed across the varying conditions present in the dataset. - interested in finding genes that are differentially expressed that are also in a module (i.e., a group of genes) that is correlated with the phenotype of interest, in this case alcohol preference.

common features of hallucinogens

- Hallucinogen: ability to evoke hallucinations or pseudo hallucinations - Psychotomimetic: ability to mimic endogenous psychosis - Phantasicum, Psychedelic: "mind-expanding"

What are the four criteria of cannabis withdrawal syndrome? What are some of the symptoms?

- Heavy and prolonged use of cannabis - Three or more symptoms occur one week after first criteria: Irritability, Anxiety, Insomnia, Decreased appetite, Restlessness, Depressed mood - One of these must cause significant physical discomfort - Second criteria inhibits or impairs social and occupational obligations - The symptoms are not attributed to another form of medical ailment -

Describe the methods and results of the experiment done relating to heroin self administration

- Heroin infusions/session vs self administration session: linear increase in number of heroin infusions/session as the number of sessions increased - Reward threshold vs self administration sessions: increase in reward threshold with increasing number of sessions (demonstrating withdrawal)

Face validity of animal models of drug abuse liability

- Humans and a wide variety of other species of animals (mice to monkeys), readily self-administer drugs of abuse via various routes of administration (egs, oral, iv, icv). - Lab animals given unlimited access to heroin or cocaine can voluntarily overdose to the point of death - parallel with human behaviour. - Mice and rats, under certain drug administration protocols, will self-administer large amounts of alcohol - again a parallel with humans.

Describe the methods and results of experiments done relating to opioid withdrawal

- ICSS thresholds determined before and after limited access to cocaine, heroin, and nicotine. All three drugs decreased reward thresholds. - Naloxone dose dependently increased ICSS threshold in morphine group but not placebo group

pharmacokinetics of psychostimulants

- IV and smoked have highest level at beginning and then slowly drops off - intranasal and oral increase gradually and then drop off- intranasal increases more quickly than oral but takes longer to drop off than oral - abuse liability is highest for rapid intake (Ex. injected, inhaled, smoked, etc), high for oral, and lowest for slow continuous absorption

Routes of Drug administration

- IV: Valuable for emergency use, suitable for large volumes and irritating substances but cant go back, increased risk of adverse effects, and must inject slowly. - Subcutaneous: suitable for some insoluble suspensions and implantation of solid pellets but not suitable for large volumes, could cause pain and possible tissue damage - Intramuscular: suitable for moderate volumes and some irritating substances but possible pain and tissue damage - Oral: Reversible, generally safe, convenient, and economical, but requires patient cooperation, erratic absorption, possible incomplete absorption, and possible instability

WGCNA (Weighted Gene Co-expression Network Analysis)

- Identify biological networks based on pairwise correlations across variables - Can be applied to most high-dimensional data sets• - Outstanding data reduction approach

Wolfram Schultz's experiments showing that dopaminergic neuron firing predicts reward

- Initially, DA cell firing rate increases after a 'surprise' reward. - After conditioning the animal learns that the conditioning stimulus (CS) such as a light predicts reward. DA cell firing rate goes up right after the CS. - initial increase in DA cell firing right after CS but failure to obtain predicted reward leads to a decrease in DA cell firing.

Describe spice and synthetic cannabinoids and their intoxication/ withdrawal effects

- Intoxication: tachycardia, hypertension, hallucinations, anxiety, seizures, psychosis - Withdrawl: agitation, anxiety, mood swings, vomiting, loss of apetite - May trigger accute or chronic psychosis - Bind with varying potencies and efficacies

Describe the neural circuits involved in opioid reward

- Intracranial self administration of morphine: LH, NAcc, AMG, PAG, VTA - IV self administration blocked by Mu antagonist in NAcc or VTA - IV self administration of heroin blocked by lesions in NAcc, PPT, and VP - at cellular level, MOR agonists reduce excitability and transmitter release at the sites indicated by inhibiting Ca2+ influx and enhancing K+ current. Thus, opioid-induced inhibition in the VTA on GABA-ergic interneurons or in the NAc reduce GABA-mediated inhibition and increase outflow from the ventral pallidum (VP), which appears to correlate with a positive reinforcing state (enhanced reward)

health consequences of alcohol consumption

- J shaped curve for ischemic heart disease (risk decreases initially then increases with higher doses of alcohol) ? - Increases risk for diabetes, breast cancer, lip and mouth cancer, stroke, and tuberculosis as well as overall health issues

Receptor Binding (affinity)

- K+1 is rate of binding - K-1 is rate of dissociation - Dissociation Constant = K-1/K+1 - Kd is free drug concentration at which half of binding sites are occupied - lower Kd means greater binding affinity - contributes to potency

Hallucinogen mechanism of action

- LSD and other hallucinogens primarily act as 5-HT2A postsynaptic receptor agonists - LSD is fairly promiscuous(5-HT1/2/5/6/7 types), Mescaline does not bind to 5-HT1/5/7, All have affinity for 5-HT2 family, 5-HT2A shows greatest expression in neocortex - Tolerance (decreased 5HT2A binding and signaling) and cross tolerance

Quantitative trait loci (QTL)

- Locus--a particular site on a chromosome. - A QUANTITATIVE TRAIT LOCUS (QTL) is a chromosomal locus containing a gene or genes influencing a complex (quantitative) trait. - While the genotypes at a QTL cannot be directly observed, they can be estimated from the genotypes present at nearby marker loci (markers) - F1 progeny generated by crossing two phenotypically divergent strains. F1 mice can be intercrossed to produce F2 progeny or backcrossed to the parental strains to produce N2 progeny. All progenies phenotyped and genotyped using informative markers across the genome. - Statistical phenotype/genotype correlations are carried out to identify genetic loci underlying the given phenotype - 1nbred strains: all animals are genetically identical - Recombinant Inbred (RI) Strains - progeny of generation of mice produced by interbreeding two inbred strains

Benzodiazepine abuse

- Low abuse liability, low preference - Schedule IV drugs, Harsher penalties for illegal distribution of flunitrazepam (Rohypnol is schedule 1) - Controversy about over-prescription

How effective are animal models?

- Major advances made in the understanding of neurobiology and psychiatric disorders. - However, preclinical studies often do not generalize to success at the clinical level. - Many pharmaceutical companies have lately terminated drug development programs in the area of psychiatry. - Schizophrenia may be more difficult to model in animals than drug abuse liability.

Pharmacokinetic tolerance

- Manifests itself in the form of upregulation of enzymes that metabolize the drug (often cytochrome P450) - Barbiturates, nicotine and alcohol produce significant pharmacokinetic tolerance following chronic administration (takes days to weeks) - Nicotine induces pharmacokinetic tolerance in specific brain regions but not the liver - MDMA inhibits its own metabolism

Generation of a congenic strain through backcrossing

- Mate two inbred strains - Back-cross descendants 5-10 generations with one of the original strains (recipient strain) - Typically, selection for either phenotype or genotype is performed prior to each back-cross generation

Phenylethylamines

- Methoxyamphetamines (Ex. DOM, MDMA, TMA, Methylenedioxyamphetamine and methylenedioxymethamphetamine) - Synthetic derivatives of mescaline - Many are so-called "designer drugs" - Structural similarity to catechol - Mixed hallucinogenic and stimulant effects

Describe the homodimers and heterodimers that opioid receptors form

- Mor-Dor dimers: ligands binding at these dimers decrease rates of internalization - Mor agonsits + dor antagonist yields analgesic activity and diminished tolerance and dependence - Can be homodimers (2 of same receptor) or heterodimers (2 of different receptors)

classification of inhalants: Gas (Nitrous oxide ; N2O; laughing gas)

- N2O is a widely used gaseous anesthetic agent, produced euphoric effect - produces an unusual spectrum of behavioural and subjective effects at subanaesthetic doses similar to those produced by stimulants, depressants and hallucinogens - Differs from volatile anaesthetics in a number of subjective effects

Ethanol and toluene inhibition of NMDA-activated currents: effect of receptor subunit mutations

- NMDA receptors composed of NR1 + NR2A-D subunits expressed in HEK 293 cells -measured percent inhibition to ethanol, 1 mM of toluene, and 3 mM of toluene in wild type, GluN2A, GluN2B (most sensitive to toluene), GluN2C, and GluN2D rats - Mutations selectively affect ethanol modulation (decreased sensitivity of the NMDA receptors) - showed that alcohol and toluene must be operating at different places

naltrexone and AUD

- Naltrexone is opioid receptor antagonist. - Greater doses of naltrexone reduce alcohol self administration - Naltrexone also increases the percent of subjects not relapsing as a function of time

Describe the therapeutic effects of cannabinoids, the goals of developing cannabinoid therapeutics, and the strategies for developing cannabinoid therapeutics

- Nausea, cachexia, obesity, pain, spasticity, neurodegenerative disease, mood disorders, and substance use disorders - Avoid psychotropic effects and avoid receptor downregulation - Allosteric agonist, optimize endocannabinoid levels, peripherally acting drugs, and modulation of non CB1/CB2 receptors

Neuropeptide Y (NPY) and alcoholism

- Neuropeptide Y-deficient mice consume more ethanol than controls while NPY over-expressors consume less ethanol. measured mean alcohol intake in preferring and non prefering rats given aCSF, 5 micrograms NPY, and 10 micrograms NPY. - NPY effective at reducing intake in dependent rats

Acute reinforcing effects of nicotine

- Nicotine can activate VTA DA neurons directly by stimulating nAChR on these neurons. - Nicotine can also act on nAChR found on glutamatergic presynaptic terminals projecting to VTA. - Lastly, nicotine may activate endogenous opioid pathways. These cells then inhibit GABAergic interneurons in VTA.

nicotine and locomotor activity

- Nicotine induces locomotor sensitization - activity vs time for saline, .1 mg/kg nicotine, and .4 mg/kg nicotine in rats that have acute vs chronic nicotine exposure - chronic exposure sensitized rats to locomotor effects of nicotine

Nicotine and DA levels in nAcc & VTA

- Nicotine infusion increases DA levels in nAcc & VTA - dopamine (% baseline) vs time in nucleus accumbens and VTA - Greater nicotine potency in accumbens

Pharmacodynamics of Nitrous oxide

- Nitrous oxide inhibits NMDA-mediated currents - N2O exhibits rapid block of NMDA receptor currents. A, Responses to 20 μm NMDA in the presence or absence of 3 μM ketamine. B, The same application protocol performed on another cell using N2O as the antagonist. Rapid development of block with co-application of agonist and antagonist. - Nitrous oxide activates two-pore-domain (TREK-1) K+ channels -Rats taught to discriminate nitrous oxide from oxygen. High and low affinity NMDA channel Blockers mimicked nitrous. Ethanol partially substituted for N2O -mice also become tolerant to N2)

Why do we need animal models?

- Olds & Milner developed ICSS technique leading to discovery that dopaminergic projections from the VTA to limbic structures such as the NAcc, mPFC and amygdala mediated this ICSS. - operant techniques for self administration of morphine - intake easy to tell but affect difficult while for humans affect is easy but intake is difficult - manipulate factors to determine how they change addiction, and can tell the directionality of this relationship EX- Rats experiencing food deprivation followed by access to food pellets/sucrose, begin to escalate sucrose intake, particularly in the first hour (binging). - show cross-sensitization to amphetamine. - upon sucrose withdrawal they voluntarily consume more alcohol

Toluene self-administration?

- Operant responding for toluene vapor or Air across 3 weeks of training. - Number of daily vapor deliveries vs day for Air and Tol rats, Tol showed greater SA - Average vapor deliveries for Air or Tol rats, greater in tol - vapor deliveries vs time during session, greater in Tol

Describe the mechanism for the analgesic effects of opioids

- Opiate-sensitive pathways in PAG Mu opiate actions block the release of GABA from tonically active systems that otherwise regulate the projections to the medulla (1) leading to an activation of PAG outflow resulting and activation of forebrain (2) and spinal (3) monoamine receptors that regulate spinal cord projections (4) which provide sensory input to higher centers and mood - Schematic of primary afferent synapse with second order dorsal horn spinal neuron, showing pre- and post-synaptic opiate receptors coupled to Ca2+ and K+ channels, respectively. Opiate receptor binding is highly expressed in the superficial spinal dorsal horn (substantia gelatinosa). These receptors are located presynaptically on the terminals of small primary afferents (C fibers) and postsynaptially on second order neurons. Presynaptically, activation of MOR blocks the opening of the voltage sensitve Ca2+ channel, which otherwise initiates transmitter release. Postsynaptically, MOR activation enhances opening of K+ channels, leading to hyperpolarization. Thus, an opiate agonist acting at these sites jointly serves to attenuate the afferent-evoked excitation of the second order neuron

describe the G protein dependent actions of opioids

- Opioid receptor agonists induce the Gi/o protein to dissociate into Gαi/o and Gβγ subunits. - Gαi/o inhibits adenylyl cyclases, which decreases cAMP production, leading to decreased protein kinase A (PKA) activity. - This then leads to inhibition of TRPV1 Ca2+ channels and voltage-gated sodium channels. - The Gβγ dimer blocks calcium channels but enhances potassium channel opening, including GIRK and KATP potassium channels - essentially, net result is inhibition of cell by opioid agonits

Describe naloxone and its effects?

- Opioid receptor antagonist (used as treatment for opioid overdose) - Reduces analgesia resulting from stimulation of periaqueductal gray

Acute reinforcing effects of opiates

- Opioids increase DA tone indirectly by inhibiting GABAergic interneurons in VTA to increase DA release by the VTA DA projection neuron. - Opioids also directly inhibit nAcc neurons (via Gi)

Explain the relation between plasma levels and weed taken orally vs smoked

- Oral administration, gradual increase in plasma levels with increasing THC dose - Smoking, sharp increase in plasma levels with increasing THC dose

PTZ and anxiety

- PTZ is a drug that produces anxiety like effects in rats by acting as an antagonist at GABAa receptors. Rats taught to discriminate PTZ and saline - measured Percent of rats pressing PTZ lever vs dose for agonist lormetazepam, ZK 95 962, CL 218 872, and CGS 9896 - agonist reduced PTZ lever responding (antagonism) - measured percent of rats pressing PTZ lever vs dose for inverse agonist DMCM, CGS 8216, and ZK 90 886 - inverse agonist increased PTZ lever responding (generalization)

GABAa receptor

- Part of complex composed of five subunits - Subunits assemble around an integral chloride (Cl-) channel - GABA increases Cl- conductance (inhibition) - Agonists: GABA, muscimol - Antagonist: bicuculline Cys Loop receptor: Large N-terminal domain (binding site for GABA), Transmembrane domain containing 4 segments (TM1-4), Large intracellular cytoplasmic domain (TM3-4 linker), Small C-terminus, Five subunits form each channel, TM2 of each subunit contributes to pore

Problems with lipid-based theories on the mechanisms of volatile anaesthetic action

- Pharmacologically-relevant concentrations of general anesthetics have minor effects on bulk membrane order and fluidity. - does not explain why some stereoisomers vary in potency. - The alcohol cutoff effect (as size of alcohol increases, point above which potency does not) - Explaining why some very lipophilic compounds appear to contradict the Meyer-Overton rule. EX: Diethyl ether has the typical depressant & anaesthetic effects expected of this class of compounds. Fluorothyl (fluoro-ethyl ether), however, is a convulsant vapour, suggesting the actions of these compounds depend on chemical structure and not just their physical properties

Acute reinforcing effects of PCP and cannabinoids

- Phencyclidine (PCP) inhibits postsynaptic NMDA receptors on cells in the NAc. - Cannabinoids, acting via CB1 receptor mediated Gi activation, produce neuronal inhibition in the NAc.

Amphetamines (& Amphetamine-likes)

- Phenethylamine (PEA): Naturally-occurring, VMAT 2 inhibitor, Mood-enhancing dietary supplement (chocolate!!) - Amphetamine (α-methyl-phenethylamine), d-amphetamine, l-amphetamine, Benzedrine: d-amph + l-amph, Dexedrine: d-amph - Methamphetamine (Methylamphetamine), Methedrine (methamphetamine HCl) - Ephedrine: Used to maintain blood pressure during spinal anesthesia, Can be used to make methamphetamine - Methylphenidate (Ritalin ®)

Physical Dependence

- Physical dependence to a drug can only be demonstrated by eliciting drug withdrawal. - Cross dependance can develop for drugs with similar effects. (Benzos can be used to ameliorate symptoms to alcohol withdrawal)

How has the ratio of delta 9 THC to cannabidiol changed over time?

- Potency of illicit canabis material has increased over time - Over time the THC concentration has increased seeing as it started with marijuana and switch to sinemelia. Meaning that over time the amount of THC in hat has been smoked has increased and the amount of CBD has decreased.

Inhalants

- Psychoactive agents with diverse chemical structures. - rank fourth behind alcohol, marijuana and tobacco in incidence of abuse in the U.S. - Profile of abusers: youths, low self-esteem, poor socio-economic background, disrupted living conditions, poor family relations, academic problems, exposure to substance-abusing peers.

how can genetics influence risk for SUD

- Psychopharmacology (reward vs aversion, innate tolerance) - personality (sensation seeking, extraversion, impulsivity) - psychopathology (depression, anxiety, antisocial personality) - physiology (metabolism, flushing)

Deep brain stimulation

- Rats allowed to self-administer cocaine and then cocaine-seeking behavior was extinguished by replacing cocaine with saline - measured total active lever responses vs cocaine dose as well as active lever responses vs time. - rats that received DBS exhibited lower levels of lever responses compared to controls

Functional tolerance to ethanol as a form of learning

- Rats trained to walk on treadmill to avoid foot shock. - Animals developed tolerance if given subsequent practice while ethanol intoxicated. - Rats given equivalent doses of ethanol after practice did not develop tolerance, neither did saline. - Tolerance not developed unless unless the response used to measure tolerance is performed while subject is intoxicated.

Negative affective state during cocaine use

- Rats were exposed to cocaine for 3-48 hours of self-administration. - Withdrawn for 0-72 hours and ICSS thresholds determined at time points indicated on X axis. - The longer the cocaine exposure duration, the greater the ICSS reward threshold increase and the longer it lasts. - Increases in ICSS reward threshold are indicative of dysphoria - also showed reward threshold vs escalation days as well as # of injections vs escalation days in ShA and LgA rats. Both greater in LgA - accompanied by long-lasting decreases in D2R expression

Sensitization to reinforcing effects of drugs

- Repeated intermittent administration of psychostimulants, opioids and alcohol can produce a long-lasting enhancement of their behavioral effects (sensitization). - May be responsible for psychosis that occurs in some people who repeatedly abuse psychostimulants. - Both self-administration approaches and CPP have been used to study the sensitization in the reinforcing effects of drugs in animals. - Rate of acquisition of psychostimulant self-administration is faster in animals that previously received noncontingent injection of psychostimulants - Cross-sensitization of reinforcing effects within the same class of drugs (ex. Prior administration of amphetamine increases rate of cocaine acquisition and vice-versa)

classification of inhalants: Volatile solvent, fuel and anaesthetics

- Representatives of this class include toluene (glue), TCE (correction fluid), butane (cigarette lighter fluid), propane (bottled fuel), chloroform & sevoflurane (anaesthetics) - Other compounds that may be abused are ketones (paints), acetone (nail polish remover), chlorofluorocarbons (Freon)

Alcohol and Cancer

- Risk of esophageal cancer slightly increased by alcohol alone, more strongly increased by smoking alone, and massively increased by both together. - potentially caused by changes in oral microbiome and acetaldehyde production

Conditioned place aversion

- Rodents are repeatedly exposed to a particular environment while undergoing drug withdrawal and a distinctly different environment when not undergoing withdrawal (analogous to CPP from last lecture). - Administration of an opioid antagonist to opioid-dependent animals triggers a dose-dependent conditioned place aversion. - conditioned place aversion produced by naloxone in morphine dependent rats - Conditioned place aversion approach also works with spontaneous withdrawal.

Does alcohol have cardioprotective effects

- Short answer is yes it dose but only at low doses. - French have a low incidence of CHD relative to their diet high in saturated fats. - Alcohol, not grape juice, reduces atherosclerosis. - At least partly due to elevation of HDL cholesterol. This could decrease mortality - and does in most studies. - BUT other effects of alcohol (accidents, violence,liver damage, etc) shorten life span.

Alcohol withdrawal

- Signs range from headache, hyperexcitability, insomnia, tremor, nausea/vomiting, sweating, anxiety to convulsions. Typically treated with quiet dark room, fluids, rest. - Delerium tremens: severe form of alcohol withdrawal typically occurring 2-4 days after last drink in individuals consuming large amounts of alcohol for months. - signs of DT include: Altered mental state, Autonomic nervous system hyperactivity, Visual and auditory hallucinations, Sweating, Hypertension, Seizures, Treatment for DTs: benzodiazepines, vitamins

Voluntary drug consumption

- Simplest experiment would involve putting alcohol in the animals' water bottle but tells little since animals need to drink the solution in order to get water. - T wo bottle choice: one bottle contains ethanol while the other contains water or isocaloric sucrose. Measure amount of fluid drunk from each bottle to obtain preference ratio. - Different lines of mice (HAP/LAP) and rats (HAD/LAD, P/NP) consume different amounts of alcohol - genetics plays a role. - Most lines of rodents don't like to drink alcohol so specific protocols have been developed to foster voluntary consumption (egs., drinking in the dark, sucrose fading procedure).

fetal alcohol syndrome

- Specific pattern of facial features - Pre- and/or postnatal growth deficiency - Evidence of central nervous system dysfunction - characterized by neurobehavioral problems (hyperactivity, learning disabilities, depression, psychosis) -Influences brain development, especially during periods of rapid neurogenesis, leading to decreased brain weight

Acute reinforcing effects of stimulants

- The dopaminergic projection from VTA to nAcc is inhibitory - D2 receptors in the nAcc activate the Gi subtype of G protein, which inhibits adenylyl cyclase activity. - Stimulants like amphetame and cocaine directly increase dopaminergic activity in NAc.

At which brain regions do opioid receptor antagonists act during ethanol administration?

- The effects of administration of the opioid receptor antagonist methylnaloxonium into the amygdala and nucleus accumbens on responding for ethanol in rats. - mean responding for ethanol vs dose measured for amygdala and nucleus accumbens - found amygdala is more sensitive brain region

neurobiology of preoccupation/anticipation stage

- The preoccupation/anticipation or drug craving stage involves the prefrontal cortex. - The role of the prefrontal cortex is to mediate executive function (planning, decision making, judgment). - Two systems: Go system engages habit systems (possibly unconsciously) while the Stop system inhibits these processes. - Interactions between these systems produces impulsivity often seen in addiction. Go system: Anterior cingulate facilitates selection of responses, planning, self-initiation and self-monitoring of goal-directed behaviors. Dorsolateral prefrontal cortex is involved in working memory, planning and strategy Stop system: Ventral prefrontal cortex is involved in response inhibition, memory retrieval and rule generation. The OFC is involved in assignment of value and integration of reward and punishment

neurobiology of withdrawal/negative affect stage

- The withdrawal/negative affect stage involves three structures of the extended amygdala: central nucleus of the amygdala, BNST, and NAc shell.These regions receive projections from limbic cortices, hippocampus, basolateral amygdala, midbrain and lateral hypothalamus. - Extended amygdala projects to VTA, VP and lateral hypothalamus. - Extended amygdala includes major components of the brain stress systems associated with negative reinforcement of dependence.

Explain how the structures of Synthetic cannabinoids affect the body and what physical effects they cause?

- They are direct agonists of cannabinoid receptors instead of partial agonist - The different chemical structures of Synthetic cannabinoids found in Spice/K2 may act unpredictably due to the variations in their chemical structures - Can cause tachycardia, agitation, irritability, delusions, hypertension, etc.

Benzodiazepine Tolerance and Dependence

- Tolerance seen to effects on unpunished responding, no tolerance to increased punished responding (sedation vs anti-anxiety effects) - Physical dependence, Precipitated abstinence, Role of long t1/2, and active metabolites (influences whether patient can fall and stay asleep but not feel sleepy in the morning)

pharmacokinetics of LSD

- Typical dose: 50-150 micrograms - microdosing: 5-20 micrograms - Effects seen within half an hour after oral administration and may last up to 20 hours. Peak subjective effects seen 2.5 - 3 hours after administration - Plasma half life is approximately 3-5 hours and metabolism is via cyt P450 enzymes

Classification of Inhalants: Volatile alkyl nitrites

- Used initially for the treatment of angina - vasodilatory and smooth muscle relaxant effects form the basis for the feelings of warmth, syncope and throbbing sensations following use - often labeled as "video head cleaner," "room odorizer," "leather cleaner,

Escalation of drug self-administration following a history of drug intake?

- Useful approach when wanting to develop animal models to study the transition between controlled moderate drug intake and uncontrolled excessive intake. - SgA rats get 1 hr access to cocaine per session while - LgA rats get 6 hr of access per session. - LGA rats showed greater intake in their first hour and total intake during multiple sessions

Animal models of the negative reinforcing effects of drug withdrawal

- Withdrawal effects after chronic drug administration are opposite to those of the initial acute effects of the drug. - These withdrawal effects can often be easily quantified - Physical dependence occurring as a consequence of withdrawal will increase the reinforcing effects of drugs - case of negative reinforcement. Rats given IAE (intermittent access to ethanol) exhibited a significant increase in ethanol intake compared with rats that were given CAE (chronic ethanol access)

Mutation of the GABA alpha2 subunit

- abolishes alcohol action in vitro - graphed gaba Responses vs ethanol in control vs mutated mice. mutation causes lower gaba response in mice - Gaba a alpha 2 knockin mice also exhibited less motor stimulation - ambulatory distance at 10 min vs ethanol dose in SL/SL and HA/HA mice, greatly reduced in HA/HA mice - also exhibited loss of ethanol conditioned taste aversion

GABAa receptor sensitivity during acute and chronic alcohol administration.

- acute ethanol exposure increases Cl- influx - chronic ethanol exposure decreases Cl- influx

brain imaging of alcoholics

- after a sip of alcohol and exposure to alcohol beverage pictures, alcoholics compared to social drinkers had increased differential brain activity in the prefrontal cortex and anterior thalamus. - After a sip of alcohol, while viewing alcohol cues compared to viewing other beverage cues, the alcoholics, but not social drinkers, reported higher craving ratings and had increased activity in the prefrontal cortex and anterior limbic regions. - Brain activity in the left nucleus accumbens, anterior cingulate, and left orbitofrontal cortex significantly correlated with subjective craving ratings in alcohol subjects but not in control subjects. - suggests alcoholics and not social drinkers, when exposed to alcohol cues, have increased brain activity in areas that reportedly subserve craving for other addictive substances.

punished responding for oxazepam

- allow learning of response, then have a period of punished responding, followed by another period of non-punished responding. - Oxazepam reduced amount of punished responding inhibition (I.E it caused more punished responding due to antianxiety effects)

Effects of chronic alcohol consumption on motor function

- area (% control) vs BAC in abstainers, light drinkers and heavy drinkers administered 0.63-0.80, 1.0-1.42, and 1.2-1.35 g/kg alcohol, respectively. - Chronic drinkers needed larger BAC to have same impairment, showing dose-dependent chronic tolerance

additional uses for psychedelics

- associated with positive mental health and prosocial outcomes - treating psychological distress associated with life-threatening diseases, treating depression, and treating nicotine and alcohol addictions - promising treatments for addiction, depression, anxiety, and other conditions (e.g., PTSD)

Crowd sourcing hallucinogenic experiences

- attempt to collect, catalog, and publish the wide variety of experiences people have with psychoactive plants and chemicals, as well as experiences with endogenous (non-drug) mystical experiences, drug testing, police interactions, meditation, etc. - similar to dreams - highest-ranking substance in terms of the similarity to high lucidity dreams was the serotonergic psychedelic lysergic acid diethylamide (LSD), whereas the highest-ranking in terms of the similarity to dreams of low lucidity were plants of the Datura genus, rich in deliriant tropane alkaloids.

The Serotonin System and Spiritual Experiences

- authors found binding potential correlated inversely with scores for self-transcendence, a personality trait covering religious behavior and attitudes - serotonin system may serve as a biological basis for spiritual experiences

Cocaine: Mechanism of Action

- blocks dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET). - stabilizes DAT in the outward-facing conformation - can also Block 5-HT3 receptor, Block Na+ channels (local anesthetic), and act as an Agonist at sigma receptors

Nicotine is rewarding and reinforcing in rats

- brain reward threshold vs dose of nicotine- nicotine reduces ICSS threshold - nicotine injections/3hours vs dose per injection- peaks and then returns to normal - injections as a function of time for different doses of nicotine- initial high rate of responding and then reduction

Relatedness and risk of addiction

- calculated relative risk of addiction to alcohol, cannabis, sedatives, and amphetamines for first through fifth degree relatives - relative risk decreased as degree of relatedness increased

Genetic analysis in animal models

- can use controlled genetic populations - can have more control over environment - can isolate single aspects of addiction for study at a given time- i.e., ENDOPHENOTYPES - can make and test specific changes (knock-out, knock-in, and transgenic animals)

cannabis and its relation to psychosis

- cannabis increases risk for psychosis development in a dose dependent manner

Harmful Constituents of Tobacco Smoke

- carbon monoxide (contributes to cardiovascular disease) - aromatic hydrocarbons (can be carcinogenic). - Tobacco-specific N-nitrosamines that are carcinogenic

Intermittent long access to nicotine

- causes escalation of intake - Daily withdrawal contributes to excessive intake associated with compulsive use - similar in humans

chronic inhalant use and brain

- chronic inhalant abuse causes brain damage and cortical atrophy/abnormalities

effect of insula damage on cigarette smoking

- damage to insula disrupts smoking addiction - _Patients classified as having had a disruption of smoking addiction if they fulfilled all four of the following criteria: (i) reporting quitting smoking less than 1 day after lesion onset, (ii) reporting that they did not start smoking again after they quit, (iii) rating the difficulty of quitting as less than three on a scale of one to seven, and (iv) reporting feeling no urges to smoke since quitting. - proportion of patients with disrupted smoking addiction was higher among both left insula-lesioned patients and right insula-lesioned patients compared with among noninsula-lesioned patients

Draw-backs to animal model genetic analysis

- definition of phenotype (endophenotype) - Inbred lines may have too few vs. too many polymorphisms

NMDA receptor antagonists in a drug discrimination test

- ethanol responding vs dose in ethanol, ketamine, and phencycladine groups - control response rate vs dose in ethanol, ketamine, and phencycladine groups - Mice were trained to discriminate ethanol from saline. - Compounds that did not substitute for the ethanol stimulus were cocaine, the H1 receptor antagonist hydroxyzine, and the anticonconvulsants phenytoin and ethosuximide. - PCP-like drugs that are antagonists of NMDA receptor-mediated neurotransmission share common discriminative stimulus effects with ethanol.

role of alpha 7 receptors and schizophrenia

- evidence of association between smoking and alpha7 nicotinic receptor subunit gene in schizophrenia patients - high dose of nicotine transiently normalizes abnormality in p50 inhibition in schizophrenic patients. - high rate of smoking in schizophrenics could be attempt to self medicate - alpha 7 nicotinic receptor is potential therapeutic target for individuals with schizophrenia

Is exercise addictive?

- exercise dependence syndrome: a clinical disorder in which athletes are unwilling or unable to alter or stop training regimens that are clearly medically contraindicated - Runners deprived of running experience withdrawal symptoms such as depression and anxiety - Running provides rewarding effects to people - positive mood changes and decreased levels of anxiety - Tolerance is seen to the 'runner's high' with higher mileage requirements over time - Rats will lever press for access to running wheels and develop CPP to cues associated with after-effects of running. - NMDA receptor system may be related to neurobiological mechanisms underlying compulsive wheel running in rodents. Three weeks of running led to increases in NR2A and NR2B mRNA levels in VTA.

toluene exposure and AMPA/NMDA ratio

- exposure to toluene could have effects on glutamate receptor synaptic strength - Changes in AMPA/NMDA ratio in VTA illustrate plasticity in reward-sensitive dopaminergic neurons following toluene exposure - measured AMPA/NMDA vs days following exposure in NAc core and NAc shell. -toluene increases ratio and increase stays the same in shell but reduces in core after exposure - also measured AMPA/NMDA vs toluene dose and also saw increase

how does PH influence drug absorption?

- for amines, protonation decreases absorption in the stomach. - For acids, protonation increases absorption in the stomach

describe experiments done regarding GAT211

- gat211 is a positive allosteric modulator - administered alone and with WIN55,212-2 (opioid receptor agonist) - GAT211 and WIN55,212-2 (orthosteric agonist) suppressed CFA-induced mechanical allodynia. GAT211 (30 mg/kg i.p.) had no effect in CB1 knockout (KO) mice. - GAT211 (ED50) shifted the dose - response curve of WIN55,212-2 leftward. - GAT211 synergized with WIN55,212-2. (D) Time course of antiallodynic efficacy of active GAT211, WIN55,212-2 and combination relative to vehicle. Doses in (mg/kg). - Reduces mechanical hypersensitivity induced by paclitaxel - Reversed by CB1 but not CB2 inverse agonist - Effective with repeated dosing - Challenge with the CB1 antagonist rimonabant (10 mg/kg i.p.) increased paw tremors in mice treated chronically with WIN55,212-2 (3 mg/kg/day i.p. X 9 days) but not with GAT211 (20 mg/kg/day i.p. X 9 days)

influence of ketamine on drug discovery in depression

- glutamatergic modulator ketamine has sustained antidepressant effects

The effect of the γ-aminobutyric acid-A receptor antagonist SR 95531 injections into the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the shell of the nucleus accumbens on responding for ethanol (EtOH) and water in nondependent rats.

- graph of responses vs SR 95531 dose in central nucleus of amygdala, bed nucleus of stria terminalis, and nucleus accumbens shell. - central nucleus of amygdala is most sensitive to effects of SR 95531

Behavioral mechanism of action of amphetamines and psychostimulants

- initial increase in motor activity that drops off at higher doses - increase in stereotypic behaviors that starts later and continues at higher doses - Examples of stereotypic behaviors: body rocking, marching in place, cleaning. - Punding: seen in chronic psychostimulant users; repetitive complex, purposeless, prolonged behaviors (egs., assembling/disassembling things, sorting objects)

Phencyclidine

- initially developed as dissociative anesthetic, illicit use began in 1967 - Common names: PCP, angel dust, crystal, horse tranquilizer - sold under many names and preparations (crystal, powder, tablet, liquid) - often misrepresented as another drug, LSD or ecstasy - taken orally, intranasally, i.v. or smoked (usually with marijuana/tobacco)

Internet/gaming addictions

- internet use can be rewarding, especially for the lonely or those lacking self-confidence or social skills - Greater addictive tendencies in boys toward video games but lots of women become addicted to online pursuits - Users who try to cut back on the time they spend on the Internet often have difficulty doing so

Effects of psychostimulants on performance

- lower doses of psychostimulants improve performance while higher doses decrease it, since behavior becomes more restrictive and repetitive. - Yerkes-Dodson Law and the "Inverted U-Shaped Curve" - complex tasks become slightly easier as arousal increases and then drops back down when arousal gets above a certain level - same goes for simple tasks but takes longer for arousal to decrease performance (complex behaviors are the first to be eliminated)

Factors influencing withdrawal severity

- mean handling induced seizure score vs hours post ethanol withdrawal. - conducted in groups receiving control, 1 ethanol exposure (single withdrawal), continuous ethanol withdrawal (single withdrawal), and 3 ethanol exposures (multiple withdrawals) - found that higher alcohol exposure and more withdrawals increases severity

transcriptome studies

- measure amount of mRNA to see what genes are being expressed - level of mRNA is positively correlated with protein expression -however, could have other factors including protein degradation, mRNA degradation, polyadenylation, codon preference, translation rates, alternative splicing, etc. - can be used to determine which genes might be involved in specific phenotypes by differential expression of certain genes

Effect of GABAA receptor antagonist picrotoxin on the anti-punishment effect of ethanol in rats.

- measure of shocks/10 minute in groups with saline, ethanol, ethanol +.5 mg/kg picrotoxin, and ethanol + 1mg/kg picrotoxin. - Picrotoxin decreases the number of shocks/10 min, demonstrating that picrotoxin counteracted the anti punishment effects of ethanol

experiment investigating acute tolerance in humans

- measured BAC, self estimated intoxication, and observed intoxication as a function of time after drinking. - repeated experiment for groups administered .33, .44, and .66 g/kg of ethanol. - At longer times, blood alcohol does not predict impairment (e.g. same BAC could have lower level of impairment)

how is cannabis withdrawal measured/investigated?

- measured mean withdrawal scores over 45 days of marijuana abstinence in current marijuana users and ex-users - conducted for many measured of withdrawal including irritability, anxiety, aggression, anger, sweating, craving, etc. - found that the withdrawal scores for these measures were almost always greater in current smokers.

tolerance to marijuana

- measured subjective high vs time after smoking in light/moderate and heavy smokers during weeks 1, 5, and 9 - also measured subjective high and heart rate over time during each of those weeks - tolerance developed to the subjective effects of marijuana

β2 nicotine receptor knockout mice

- nose poke responses vs self administration session - B2 ko mice wont self administer nicotine and cant discriminate

lush

- odorant binding protein in Drosophila. - Directly binds ethanol and protects flies from high concentrations of ethanol

Describe the methods and results on the effects of heroin on pain threshold

- paw pressure required to induce ultrasonic vocalization vs time after heroin administration - Increase in paw pressure directly after heroin administration but great decrease in period a little while after - supports development of opponent processes after a single injection of heroin

Effects dopamine receptor antagonist fluphenazine in the nucleus accumbens in nondependent rats on ethanol and water responding

- percent responding for ethanol vs fluphenazine concentration and percent responding for water vs fluphenazine concentration. - Ethanol responding gradually reduced with increasing fluphenazine concentration. Responding for water also decreased at highest fluphenazine concentration.

anaesthetic potency and potency in inhibiting firefly luciferase

- potency for general anesthesia vs potency for luciferase inhibition - demonstrated positive correlation - firefly luciferase is not membrane bound, showing that there could be a lipid like pocket in the protein that these compounds could be acting on

Gloeobacter violaceus pentameric ligand-gated ion channel homologue (GLIC)

- resistant to ethanol modulation (% modulation vs ethanol concentration) - Substitution of phenylalanine with smaller/more polar residues at 14' correlates with enhanced alcohol potentiation (% modulation vs ethanol concentration with mutated channels) - The first structural study showing an ethanol site in an ion channel F14'A structure confirms inter-subunit binding

Competitive antagonism

- reversible binding of agonist and antagonist at common binding site. - increases EC50 but does not change max response.

irreversible antagonism

- reversible binding of agonist but irreversible binding of antagonist at common binding site - no effect on EC50 but reduces max response

Overview of the Genetics of Alcohol Use Disorder

- several potential genetic susceptibility factors for AUD have been identified, but the genes of alcohol metabolism, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), have been found to be protective against the development of AUD - GWAS have identified a heterogeneous list of SNPs associated with AUD and alcohol-related phenotypes but many of these findings have small effect sizes when compared to alcohol metabolism genes - Although studies spanning multiple approaches have suggested a genetic basis for AUD, identification of the genetic risk variants has been challenging. Some promising results are emerging from GWAS studies; however, larger sample sizes and improved technology are needed to improve GWAS results and resolution

drug discrimination

- test whether different drugs have similar stimulus effects. - determine threshold doses/ concentrations of drugs that can be reliably distinguished from saline. - investigate generalization among different drug classes (Zolpidem generalizes to ethanol in discrimination experiment) - investigate receptor specificity in drug discrimination (rats administered Rimonabant (SR141716) (CB1 receptor inverse agonist) cant discriminate THC) Relies on two hypotheses: 1. Drug actions are perceived similarly by animals and humans. 2. Discriminative stimulus effects of drugs contribute to drug taking in intermittent users and to relapse in former addicts

experiment investigating acute tolerance in rats

- time off belt vs brain ethanol level at 9-11 min post injection, 29-31 post injection, and 54-61 min post injection. - ethanol levels required to produce a given level of impairment increases markedly with time after injection. This is single dose or acute tolerance.

Comparison of inhalants to ethanol

- toluene, 1,1,1-trichloroethane, and oxazepam produce ethanol like discriminative effects - tolerance and sensitization to 1,1,1-trichloroethane- increases in activity at lower concentrations and decrease at higher concentrations. Tolerance developed to grip strength, inverted screen, and number of rears. Sensitization occurred to measures of locomotor activity. - acute toluene exposure induces CYP2E1 (tolerance)

Gambling addiction

- vary in gambling behavior, the severity of their gambling problems, gambling treatment histories, biochemistry, consequences of gambling, personalities, other disorders and psychiatric difficulties, psychiatric histories, substance abuse and family backgrounds. - speculated that the underlying pathology in pathological gambling is a reduction in the sensitivity of the reward system - reduction of ventral striatal and ventromedial prefrontal activation during guessing game was observed in the pathological gamblers that was negatively correlated with gambling severity - Monetary reward blackjack was associated with significantly higher relative metabolic rate in the primary visual cortex, cingulate gryus, the putamen and prefrontal areas 47 and 10, compared to blackjack playing for points only, confirming the salience of monetary reward in the development of pathological gambling - strong evidence for genetic contributions to the development of pathological gambling in men - variety of effective pharmacological treatments for pathological gambling have been shown to have efficacy including giving patients SSRIs, opioid antagonists, and lithium - In pathological gambling there is also evidence for abnormal levels of dopamine - abnormalities in mesolimbic brain structures could result in an abnormal arousal regulation in pathological gambling, resulting in longer play, either through higher arousal, leading to disinhibition, through overall lower arousal levels which encourage thrill seeking behavior to heighten arousal, or through the absence of higher arousal when losses are experienced

Korsakoff psychosis

-Largely irreversible -symptoms: apathy, emotionally detached, anterograde and retrograde amnesia, confabulation. -Due to damage in dorsal thalamus and mammillary bodies. - Other triggers include head injury, thalamic or subarachnoid hemorrhage and occasionally tumors involving the posterior thalamic region

Cirrhosis (Scarring, nodules)

-Late stage liver disease -Manifests as inflammation, fibrosis, necrosis -Acetaldehyde may be responsible for fibrosis due to enhancing collagen deposition -Morbidity common (jaundice, liver enlargement, ascites, bleeding, cachexia, infections, encephalopathy) -largely irreversible, treat by liver transplant

Steatohepatitis (Fat + inflammation & injury)

-Less common than steatosis -Alcohol is not the only cause -Precursor of cirrhosis but can occur in cirrhotic patients -Signs: jaundice, ascites and hepatic encephalopathy, Changes in liver enzymes (high aspartate aminotransferase to alanine aminotransferase, AST:ALT ratio), multi-organ failure, and death

Acute model of alcohol physical dependence

-Two common mapping populations are derived from the two inbred mouse strains (progenitors): C57BL/6 (B6) and DBA/2J (D2) - A single large dose of alcohol is given by injection (4.0 g/kg, i.p.) - Withdrawal signs are assessed 4-12 hours later - Peak withdrawal intensity is at 6-8 hrs post-injection when blood alcohol levels are at or near zero

Illicit Use of Barbiturates

-Used for effects similar to alcohol -Often used with other drugs - with stimulants or opiates - Impairment with alcohol - Rapid tolerance - Severe withdrawal reaction - Low safety margin - respiratory depression - drug-related suicides

Why use inhalants?

-Very fast high (correlation between drug use and its reinforcing effects) -No pain (no needles) -Drug removed from body by exhalation ( magnitude and duration of the 'high' can be controlled)

methanol

-broken down into formaldehyde and formic acid - formaldehyde and formic acid are toxic to the optic nerve leading to irreversible blindness - Treatment with fomepazole (ADH inhibitor) or ethanol given soon after poisoning.

Wernicke encephalopathy

-largely reversible, caused by thymine deficiency -symptoms include confused state, gait ataxia, abnormal eye movements -Treatment: i.v. thiamine infusions

Acamprosate and alcohol administration

-measured alcohol intake vs days -effects of different doses of acamprosate administered twice daily on the first two days following alcohol abstinence (indicated by arrows) in rats intermittently exposed to a free choice of water and three different alcohol solutions (5, 10, and 20% v/v) for eight months. - acamprosate most effective after a period of abstinence, suggesting it might be most useful for maintaining abstinence - however, effects of calcium acamprosate seen in study may be due to calcium instead of acamprosate

Approaches to complex trait genetics

1) Gene-driven approaches (forward genetic approaches): Seeks to find the genetic basis of a phenotype or trait: - GWAS, quantitative trait loci (QTL) analysis, and global gene expression screens 2) Trait-driven approaches (reverse genetic approaches):Seeks to find what phenotypes are controlled by particular genetic sequences: - human polymorphisms, genetic engineering in animals (knockouts, knockins, transgenics, CRISPR)

Medical uses of barbiturates

1. Anticonvulsant (phenobarbital) 2. Anesthetic induction (thiopental) - replaced by propofol. No longer used as: sedatives, treatment for alcohol withdrawal, or anxiolytics

Animal studies demonstrating reinforcing properties of anabolic steroids

1. Conditioned place preference in mice and rats (including testosterone injections directly into the n. accumbens). 2. Self-administration: (a) oral self-administration of testosterone by hamsters seen in two-bottle choice and food-induced drinking; (b) iv testosterone self-administration in rats and hamsters; (c) icv testosterone self-administration directly into lateral ventricles. - hamsters will undergo binges that lead to death- suggest that steroids are addictive

advantages for animal models of drug use

1. Control of environmental context of drug exposure 2. Control of genetics (and use as an experimental variable) 3. Allow one to assess behaviour before and after drug administration 4. Allow for selective manipulation at specific brain regions using ligands/optogenetics 5. Gain information about brain regions, circuits, cells, neurotransmitters, etc involved in drug use/abuse 6. Allow investigators to study different stages of drug abuse cycle (initiation, maintenance, binging, tolerance development, drug withdrawal)

Complications of Chronic Alcohol Abuse

1. Females twice as vulnerable to organ damage as males 2. Cirrhosis. (Dose dependent, but also environment and genetic factors) 3. Accidents, violence, incarceration, suicide 4. Cancer: Esophageal (esp smokers), Breast (small increase) 5. Cardiomyopathy 6. Brain damage - partially reversible loss of white and grey matter

why do inhalants appeal to kids?

1. Inexpensive 2. Legal 3. Readily available 4. Discrete, easily concealed packaging 5. High occurs rapidly and disappears quickly

Mechanisms of action of inhaled drugs of abuse

1. Inhibition of NMDA receptor function. - NMDA receptors composed of the NR1 + NR2B subunits appear to be particularly sensitive to inhibition by inhalants including toluene, benzene, ethylbenzene, propylbenzene, TCE and nitrous oxide. - AMPA receptors composed of R1 or R1+R2 subunits, or R6 kainate receptors are largely resistant to toluene 2. enhancement of GABA and glycine - 1,1,1-trichloroethane reversibly enhances GABA-mediated synaptic currents in hippocampal CA1 neurons - measure gaba ipsc area vs time during TCE administration, increases - Toluene, trichloroethane and trichloroethylene enhance GABAA- and glycine-mediated currents - measure gaba and glycine current before and after administration of TOL, TCE, and TCY - Toluene enhances GABAergic function in PFC neurons - measure peak amplitude vs time in sham, .3 toluene, and 3 toluene - toluene also has pre and post synaptic effects on neurons (greater frequency of mIPSC's, indicating that there is more neurotransmitter release going on from presynaptic cells)

Toxicities Associated with Inhalant Abuse

1. Neurological - CNS most vulnerable system to inhalants. can lead to irreversible cognitive deficits. Toluene, Gas sniffing, hexane, and ketone all exhibit drastic neurological effects 2. Cardiovascular - sudden sniffing death syndrome (SSDS) caused by inhalants that sensitize the myocardium to adrenaline, particularly associated with the abuse of butane, propane, and chemicals in aerosols. 3. Pulmonary - asphyxiation (hypoxia) and direct damage to pulmonary tissue 4. Hepatitis - metabolism of chlorinated hydrocarbons in liver leads to toxicity as well as Kidney damage 5. Malignancies - chronic abuse of benzene shown to cause bone marrow suppression, lymphoma, and multiple myeloma. 6. Teratogenicity - similar to FAS.

Possible Mechanisms of Action for indirect sympathomimetics

1. Promoting neurotransmitter release 2. Blocking neurotransmitter reuptake 3. Blocking neurotransmitter metabolism

pharmacological and behavioral properties common to inhalants and other CNS depressants

1. Psychomotor impairment 2. Anticonvulsant properties 3. Enhancement by EtOH 4. Biphasic effects on locomotor activity 5. Anti-anxiety effects 6. Cross-dependence with ethanol 7. Ethanol- or barbiturate-like discriminitive stimulus effects 8. Reinforcing effects.

potential issues with ICSS

1. Requirement for surgery to implant electrodes. 2. Degree of ICSS observed depends on brain region (reward circuits) have been selected. 3. Need to train animals for several weeks to obtains stable ICSS baselines of responding as well as thresholds of responding. 4. Possible issues of drugs on motor or performance capability. These have been addressed by methodologies such as the rate-frequency curve-shift procedure.

limitations of animal models of drug use

1. Risk of anthropomorphizing - is the animal consuming the drug for the same reasons a human would? 2. Animal models do not reproduce social and personal reasons for drug abuse by humans.

The first links of tobacco to cancer

1761- London botanist John Hill claimed nasal cancer can be caused by the overuse of snuff (never substantiated). •1939 - Franz Hermann Müller found those with lung cancer were more likely than non-cancer controls to have smoked cigarettes.

Describe the methods and results of both experiments conducted on the effects of naloxone on conditioned place aversion

1st- conditioned place aversion affects naloxone after single dose of morphine - Rats given naloxone spend less time in conditioned compartment Rats given saline spend more time in conditioned compartment hoping they will receive morphine 2nd- conditioned place preference of rats with brain regions - At lower doses of antagonist, the amygdala and nucleus accumbens had a faster reduction of of time spent in the conditioned box.

Reinstatement of extinguished drug-seeking behavior in an animal model of relapse: use of discriminative stimuli.

A discriminative stimulus (S) is paired with response-contingent drug delivery; i.e., the discriminative stimulus signals the availability of the reinforcer. These discriminative stimuli may play a role in craving as a component of human craving is cognitive awareness of drug availability.

Boundary Model of Tobacco Use

A: Sum of all aversive biological consequences of nicotine B: range of indifference to pharmacological properties of nicotine C: Sum of all biologically based pressures to smoke.

Incidence of Smoking and Drinking

About 10-13 % of Americans are dependent on alcohol. About 70% of alcoholics are heavy smokers; compared with ~20% of general population 35% of smokers are alcoholics, only 10% of general population

What is vitamin E acetate related to? What effects does it have?

Additive found in some THC containing E cigaretes. Closely associated with EVALI

sedative hypnotics and anxiolytics

Alcohol, Barbiturates, Benzodiazepines, Non-benzodiazepine sedatives

advantages of RNA-Sequencing:

Allows the detection of: all known and novel RNAs without bias toward known transcripts, coding and non-coding RNAs, alternative splicing events, expressed single nucleotide polymorphisms (SNPs) Flexible library preparation: whole transcriptome, gene selection

What is the basic research done on cannabinoids?

Amyloid formation, Hypertension, Diherrhea, Sleep apnea, and huntington's

construct validity

An assessment of the model. Does it measure what it is purported to measure? Does the animal model represent the brain regions/circuits/ neurotransmitters that are involved in drug abuse pathology in humans?

Other addictions

Anabolic steroids, Activities (sex, exercise, Internet, shopping, etc), Gambling, and tanning addiction

behavioral effects of amphetamines

Analeptic (awakening), Arousal, Alertness/Vigilance, Decreased fatigue, Motor stimulant, focus

Are androgens truly reinforcing?

Anecdotal evidence that greater doses are taken in successive drug cycles, Users experience a "crash" after cycles, Some reports of euphorigenic effects of anabolic steroids

Receptor gating (efficacy)

B= rate of receptor activation A=rate of receptor desensitization Efficacy=B/A - contributes to potency - Has to do with max response

Adverse effects of hallucinogens

Bad 'trips' - possibly triggering psychosis Flashbacks Hallucinogen persisting perception disorder (HPPD)

mechanisms of action for BZ vs Barbs

Barbiturates: increase duration of open states, no change in number of openings Benzodiazepines: increase opening frequencies, no change in duration of openings

Sedatives/Anxiolytics

Benzodiazepines (Ex: diazepam, lorazepam, midazolam, Alprazolam, etc.) Non benzo sedatives (Ex: Zolpidem, Eszopiclone, and Zaleplon)

Describe the influence of the knockout of the various opioid receptors and roles of various endogenous opioids?

Beta endorphin - Receptors: MOR - Effects: analgesic Met and leu encaphalin - Receptors: DOR > MOR - Effects: analgesic, antidepressant, anxiolytic Dynorphin A, B, neoendorphin - Receptors: KOR - Effects: mixed effects on pain - aversive Endomorphins - Receptors: MOR - Effects: analgesic Mu: decreased locomotion, increased nociception, and decreased anxiety Delta: increased locomotion and anxiety Kappa: increased nociception

addiction cycle

Binge/Intoxication -> Negative Affect/Withdrawal -> Preoccupation/Anticipation ->

describe the behavioral effects of knocking out the CB1 receptor

Blocks analgesic, locomotor suppressing, reinforcing, and dependence inducing effects of cannabinoids

Physiological effects (Cocaine)

Bronchial dilation, Pupillary dilation, Glandular secretion decrease, tachycardia, and increase in blood pressure (systolic), vasoconstriction, and local anesthetic effects

catecholamines vs indolealkylamines

Catecholamines include dopamine and Norepinephrine indolealkylamines include serotonin

Adverse effects of MDMA

Central nervous system symptoms: panic attacks, hallucinations, confusion, impaired judgment, insomnia, irritability Autonomic nervous system symptoms: Tachycardia, Hypertension, Mydriasis, Dry mouth, Sweating, Ataxia

health consequences of exposure to second hand smoke

Children: middle ear disease, respiratory symptoms, lower respiratory illness, sudden infant death syndrome adults: stroke, nasal irritation, lung cancer, coronary heart disease, and reproductive effects in women

Explain the requirements for the New Mexico Medical cannabis program

Chronic pain, boared-certified specialist certification Ptsd, medical records or clinical notes from phsychiatrist Glaucoma, medical records from opthamologist Arthritis, certification from rheumatologist Hepatitis c, record of current antiviral treatment Neuropathy, current medical records

Describe the tolerance and down regulation of CB1 receptors

Chronic use leads to downregulation of CB1 receptors

pharmacokinetics of nicotine

Cigarettes are very efficient delivery devices (show greatest rise in the shortest amount of time and fast reduction), Absorption is pH dependent, Alkaline pH of oral preparations favor more rapid absorption. Individuals titrate nicotine dose throughout daytime hours, Carboxyhemoglobin levels follow.

DSM-5 criteria for SUD

Cluster 1: impaired control 1. Substance often taken in larger amounts or over longer period than intended 2. Persistent desire or unsuccessful efforts to limit use 3. Great amount of time spent getting substance or recovering from its after effects 4. Craving Cluster 2: social impairment 5. Recurrent use leading to failure to perform major roles at work, school or home 6. Continued use despite negative social consequences 7. Important social, occupational, or recreational activities reduced because of use Cluster 3: risky use 8. Recurrent use in situations in which substance use is physically hazardous (eg. drunk driving) 9. Continued use despite negative health consequences Cluster 4: Pharmacological Criteria 10.Tolerance 11.Withdrawal

crack cocaine vs cocaine hydrochloride

Cocaine = Cocaine.HCl -> Soluble in water Crack = cocaine.HCL + NaHCO3 -> insoluble in water

Describe the role of conditioned positive reinforcement and conditioned negative reinforcement in opioid use?

Conditioned Positive: Cues paired with drug use can alleviate withdrawal symptoms (seek out drug related cues to alleviate withdrawal) - Resistance to extinction - Blockade of withdrawal - Relapse Conditioned negative: Cues paired with aversive events can evoke symptoms of withdrawal (avoid cues that increase withdrawal symptoms) - Conditioned withdrawal - Motivated state - Relapse

Dopamine receptor families

D1-like family: D1, D5 D2-like family: D2, D3, and D4 - D2R play a role in regulatory processes that normally limit high-dose cocaine intake.

What are the long term effects of cannabis on brain structure?

Decrease in grey matter volume in the medial temporal cortex, temporal pole, para-hippocampal gyrus, left insula, and orbitofrontal cortex

why was cocaine not originally thought to be addictive

Definition of addiction only included tolerance and withdrawal and Cocaine withdrawal does not produce obvious physical withdrawal symptoms

How does withdrawal differ in longer lasting drugs?

Delayed onset, longer lasting, smaller intensity of withdrawal symptoms

Methods for regulation of receptors

Desensitization, internalization, and downregulation

DALY

Disability-adjusted life years: sum of years of life lost due to premature mortality in the population and the years lost due to disability for people living with the health condition or its consequences.

facial features associated with FAS

Discriminating features: short palpebral fissures, flat midface, short nose, indistinct philtrum, and thin upper lip associated features: epicanthal folds, low nasal bridge, minor ear anomalies, and micrognathia

medicinal uses of tobacco

Disinfection with smoke, Mixed with chalk to whiten teeth, Skin infections, Upper respiratory infections, Local pain relief

definition of psychostimulants

Drugs that produce behavioral activation - increased arousal - increased alertness - increased motor activity

Potency

EC50 value - concentration at which the drug reaches half of its maximal response lower EC50 = more potent

Barbiturates

EX: Barbituric acid, Barbital, Phenobarbital Classes: Long (8-12 hr, Ex. phenobarbital) Intermediate (2-8 hr, Ex. pentobarbital) Short (1-4 hr, Ex. Secobarbital) Ultra-short (5-30 min, Thiopental)

Mechanism of Action of benzodiazepines (and barbs?)

Early studies: many transmitter systems implicated, nonspecific membrane effects, potentiation of GABA effects Discovery of BZ binding sites: concentrated in newly evolved structures (cortex, HC, amygdala), correlate with anxiolytic effects, closely related to GABAA receptor sites (Co-localization of BZ and GABAa receptor binding)

Signs and symptoms of nicotine poisoning

Early: Salivation and sweating, Nausea and vomiting, Eye irritation, Headache, Tremor, Dizziness, Anxiety and restlessness, Tachycardia and hypertension, Tachypnea Later: Hypotension, Bradycardia, Hypopnea, Diarrhea, Fatigue, Weakness, Pallor severe: seizures, coma, respiratory failure

Genetic and Environmental Risk Factors for Addiction

Environmental: Alcohol or drug exposure (REQUIRED), stress, Early drug or alcohol use initiation, Peer groups, Societal views of drugs and alcohol, Drug availability, and Socioeconomic status Genetic: Twin and adoption studies (risk is 30% - 80% genetic depending on substance. Alcoholism is 50%), Genetically modified or selectively bred rodents, AUD and other addictions are monogenic

What are the unexplored but possible effects of cannabinoids?

Epilepsy, hiccups, Bipolar, Alzheimers, Alcohol dependence

metabolic breakdown of ethanol

Ethanol -> acetaldehyde by alcohol dehydrogenase acetaldehyde -> acetate by aldehyde dehydrogenase

Behavioral effects (Cocaine & Amphetamine)

Euphoria, Analeptic (awakening), Arousal, Alertness/Vigilance, Decreased fatigue, Motor stimulant, Focus, Decrease in appetite

Behavioral effects of marijuana intoxication.

Euphoria, Perceptual changes, Sedation, Motor impairment, Decreased mental performance, Increased appetite, and analgesia

Describe the symptoms and signs of opioid intoxication?

Euphoria, sedation, analgesia (pain relief), pruritus (itching), miosis (contraction of the pupils), constipation, red sclerae (red eyes), respiratory depression, stupor and coma, hypotension (low BP)

Where in the brain are CB1 receptors located

Everywhere

meds for craving stage

Existing meds: Acamprosate, Buproprion Future meds: CRF1 antagonists, Glutamate modulators, GABA modulators

meds for binge/intoxication stage

Existing meds: Disulfiram, Naltrexone, Methadone, Varenicline, Buprenorphine Future meds: Partial agonists, Vaccines

meds for withdrawal/negative affect stage

Existing meds: Methadone, Nicotine, Varenicline, Buprenorphine Future meds: CRF1 antagonists, κ-opioid antagonists, GABA modulators

Explain the trends in marijuanna use from 1965-2000

For both 18-25 year olds and 12-17 year olds the use of cannabis peaked in the mid 70's, dipped in the early to mid 90's, and finally increased again toward the beginning of the 2000's

Describe the G-protein independent actions of opioids- promotes internalization

GRKs and PCK lead to phosphorylation of opioid receptors that are then recognized by B Arestin and internalized - leads to reduction in opioid receptor levels in the membrane

CNS effects of inhaled agents

General CNS depression, Low-dose locomotor activation, Anticonvulsant effects, Dizziness, Euphoria, Motor impairment, Altered sensorium and behavior, Tolerance, and Dependence

Describe the grades of opioid withdrawal?

Grade 0: craving Grade 1: yawning, perspiration, lacrimation (teary eyes) Grade 2: tremors, muscle twitches, hot and cold flashes Grade 3: nausea, restlessness, increased temperature, increased blood pressure Grade 4: vomiting, diarhea, weight loss, etc. Heroin produces withdrawal symptoms over a shorter amount of time compared to morphine and methadone due to the fact that it is the fastest acting

breeding of mice that achieve high BAC

HDID - high drinking in the dark HS/Npt - a control line of mice - HDID mice showed Gradual increase in blood alcohol concentration but did not increase consumption of sucrose, quinine or saccharin - Predictive validity examined by acamprosate administration. Acamprosate reduced intake at higher dose. Did not reduce either water or saccharin intake during subsequent tests (control). - can be used to asses genetic signature for genetic risk for alcohol abuse by looking at genes in alcohol preferring HDID rats

Describe the biotransformation pathway of heroin?

Heroin -> 6-monoacetyl morphine -> morphine -> morphine 3-B-gluguronide + morphine 6-B-gluguronide

Using Gene Expression Studies to Identify Treatments

Hypothesis: Drugs producing gene expression signatures opposite to addiction signatures will "correct" maladaptive behaviors

Explain the differences in time course and ranked high people got from oral, intravenous, and smoked weed?

IV: largest "high", shortest amount of time Smoked: still a large high reached in a still short amount of time (curve slightly under IV) Orally: not as big of a high reached, and the peak of it is reach significantly later than IV and smoked.

Functional cross tolerance among drugs

If two drugs produce similar pharmacological effects by similar mechanisms, tolerance that develops to one drug would confer some tolerance to the other, even if the subject has never been exposed to the second compound.

New approaches for treating substance use disorders

Immunization, Electroceuticals (TMS and DBS), Novel drugs against targets involved in dependence

Functional Tolerance to Ethanol

In mice: - Acquisition of ethanol drinking, Ethanol group had a trend for fewer hindslips and Water controls following ethanol administration - BECs did not differ between Ethanol and Water groups immediately following balance beam testing. In drosophila: - The sensitivity to ethanol vapor measured using an inebriometer (column that separates flies based on their ability to maintain postural control) - At standard ethanol concentration, wild-type flies "eluted" with a normal distribution - When these flies were reintroduced into the inebriometer 4 hr after the first exposure, their elution profile was also normal but shifted to the right, corresponding to increase in resistance

Major classes of hallucinogens

LSD Family - indole type hallucinogens - structural similarity to 5-HT (serotonin) - LSD (lysergic acid diethylamide)

Effects of PCP

Low dose (1-5 mg): alcohol-like effect (giddy drunken-like state, disinhibition) Moderate dose (5-10 mg): distortion of space & time, psychotic reactions (panic, agitation, depression, catatonia, paranoia), detachment from self and environment, anesthetic and analgesic effects, blank stare, amnesia, mutism High dose (> 10 mg): model of acute schizophrenia (can last up to 1-7 days with high doses), sometimes violent/aggressive behavior, exaggerated strength, feelings of invulnerability Overdose: Agitation, convulsions, coma, hypertension, psychosis

Effects of low vs. high doses of weed

Low doses: Disinhibition, Euphoria, Changes in sensory perception, Memory impairment, Balance impairment, Decreased strength, Muscle impairment High doses: Hallucinations, Synethesia, Impaired judgement, Pronounced motor impairment, Anxiety, Disorganized thoughts, confusion/paranoia

Ecstasy and Brain 5HT

MDMA causes loss of 5-HT neurons in animals (long term pruning) MDMA users have memory loss and higher levels of 5HT2A receptors in brain and these two effects are correlated.

What are the 4 forms of delta 9 THC? Which has the highest content of delta 9?

Marijuana: leave stems, tops of cannabis Sinsemelia: flowers of cannabis plants Hashish : dried resin flowers from cannabis Has oil (highest delta 9 content): soaking leaves and flowers in alcohol and then evaporating the alcohol

modern vs traditional drug discovery

Modern drug discovery: Literature and database data mining methods, in vitro or in vivo screening, Structure-based ligand discovery, Computational techniques to link diseases and drugs based on a drug's molecular effects (e.g., gene expression, interaction profile, chemical structure) Traditional discovery - Serendipity: disulfuram - Pharmacology of abused drugs: varenicline/methadone - New uses for neuropsychiatric medications: buproprion

monogenic vs complex diseases

Monogenic disease: A variant in a single gene is the primary determinant responsible for most of the disease risk or trait variation, with possible minor contributions of modifier genes or environment. Complex disease: Many variants of small effect contribute to disease risk or trait variation, along with many environmental factors. - determined by many genes (polygenic), and often by many environmental inputs as well. - Range in scope from the function of a given protein to the function of the organism. - Seen as a continuous distribution in a population rather than a discrete one.

Explain how lipid solubility explains compound uptake into the brain

More lipid solubility = greater brain uptake Heroin has the highest solubility (next to codeine) so it gets take up more easily.

compare and contrast the 3 different types of opioid receptors

Mu: analgesia, euphoria, physical dependence, sedation, resp depression, constipation, miosis. - B-endorphin, enkephalin - Agonists: Morphine, hydromorphone, methadone, fentanyl - Antagonist: Naloxone and cyprodime Delta: analgesia, physical dependence, respiratory depression, and antidepressant effects (potentially in humans?) - B-endorphin, enkephalin - Agonist: Adl5859, azd2327 - Antagonist: Naltrindole and naloxone Kappa: analgesia, dysphoria, hallucinations, dissociation - Dynorphin - Agonist: Butorphanol, U50488 - Antagonist: Naloxone and norbinaltorphimine

How do opioid antagonists relate to cannabinoid withdrawal? How do we know?

Naloxone administration induced cannabinoid withdrawal - meausred withdrawal score after naloxone and rimonibant administration - both increased withdrawal score

Cocaine

Naturally-occurring alkaloid in leaves of Erythroxylon Coca 1855, Friedrich Gaedcke: identified alkaloid extract of cocoa leaf he called erythroxyline 1859, Albert Niemann: isolated cocaine and wrote that it produced a "numbness" when applied to the tongue

Nicotine metabolism

Nicotine (4%) -> nicotine-n-oxide -> urine Nicotine (9%) -> urine Nicotine (70%) -> cotinine -> urine (10%) and other metabolites ( 60%)

Structure of nicotinic acetylcholine receptor (nAChR)

Nicotine activates, then desensitizes α2, α4, α7 receptors. Chronic desensitization induces receptor upregulation

general process of behavioral sedation

Normal -> Anxiety relief -> Disinhibition -> Sedation -> Hypnosis (sleep) -> General anesthesia -> Coma -> Death - benzos on their own are not lethal

alcoholic liver disease progression

Normal -> steatosis -> steatohepatitis -> cirrhosis

Therapeutic use cocaine

Ophthalmic surgery, Local anesthetic

Describe the classes of opioids in clinical use and their therapeutic uses?

Opioid agonists: Morphine, codeine, hydrocodone, methadone, tramadol Opioid agonists-antagonists or partial agonists: Buprenorphine, butorphanol, nalbuphine Opioid antagonists: Naloxone and naltrexone Combinations: Buprenorphine/Naloxone (Suboxone)

Medical uses of sedatives

Pathological anxiety, Severe emotional distress, Relief from agitation and alcohol withdrawal, Sedation (sleep-inducing), Presurgery sedation (midazolam), Anesthetic induction (propofol), and jet lag

Pharmacokinetic vs pharmacodynamic tolerance

Pharmacokinetic tolerance - enhancement of drug metabolism, primarily by the liver. (same level of impairment with different initial concentrations) Pharmacodynamic tolerance - Due to a decreased effect of the drug in the CNS. (decreased effect with same concentration)

Pharmacokinetics vs Pharmacodynamics

Pharmacokinetics: has to do with concentration of the drug and is influenced by absorption, metabolism, excretion, and distribution of the drug Pharmacodynamics: has to do with mechanism of action, independent on concentration

Phases of cocaine withdrawal and relapse in outpatients

Phase 1, crash: peak craving, intense dysphoria, insomnia, irritability, anxiety phase 2, withdrawal: anhedonia, decreased energy, and limited interest in environment. Highest rate of relapse Phase 3, extinction indifinite: brief episodic craving, cue induced craving Inpatients do not show these three phases. They show high mood-distress and craving that decrease over weeks

What are some cannabis constituents?

Phytocannabinoids Delta 9 THC Canabidiol (CBD) (Not psychotropically active)

Features of tobacco use disorder

Positive effects: - increased arousal, attention, learning, reaction time, and problem solving - reduced anxiety, stress and appetite Tolerance to nausea Well defined withdrawal syndrome: - craving, irritability, anxiety, difficulty concentrating, depressed mood, insomnia, hunger Common associated diseases (lung, CV, cancers) Giving up social activities: smoking in restricted areas Rare failure to fulfill work or home obligations

effects of long term anabolic steroid use

Preoccupation with drug use, Difficulty stopping despite psychological side effects, Drug craving, Acute hyperadrenergic withdrawal symptoms responsive to steroid replacement

How effective is cognitive behavioral therapy?

Project MATCH (1989-1997) - Compared CBT, Motivational enhancement, 12-step facilitation - All equally effective - 30% abstinent at 1 year

Pros & cons of replacement therapies

Pros: Prevents cravings and withdrawal, Does so without producing euphoria, Allows people to return to work, Reduces risk of disease from IV use, Reduces re-incarceration, economic and social stressors Cons: Does not reverse neuroadaptations, Can be difficult to taper, Risk of relapse

Compare and contrast purposive symptoms vs non-purposive symptoms?

Purposive: goal oriented toward getting more drugs (actively seeking drugs) non-purposive: somatic signs (contracted pupils, constipation, etc.)

Topiramate

Rationale: - Ethanol-like effects: - Enhances GABA-A receptor function• Inhibits glutamate receptors (NMDA and AMPA) Limitations: Moderate effect size, Fewer % drinking days, Fewer % heavy drinking days, Fewer drinks per drinking day Side effects: paresthesia, dysgeusia, anorexia, impaired cognition, nervousness, dizziness, pruritus - might also be useful for treatment of opioid and cocaine use disorders

Baclofen for alcohol use disorder

Rationale: - GABAB receptor agonist - Reduces drinking in rodents - Attenuates symptoms of alcohol withdrawal in humans Limitations: Meta analysis - Meta analysis: No difference from placebo in return to any drinking, percentage of days abstinent, percentage of heavy drinking days. - Evidence for increased number of drinks per drinking day Side Effects: vertigo, somnolence, paresthesia, muscle spasms.

Varenicline for alcohol use disorder

Rationale: - Partial agonist of a4b2, a3b2, and a6 nicotinic cholinergic receptors - High co-occurrence of both addictions: 56% of heavy drinkers smoke; 61% of smokers report binge or heavy drinking - Reduces ethanol consumption and ethanol-stimulated DA release in rodents Limitations: moderate effect size - RCT 200 smokers/non-smokers with AUD: reduced percent heavy drinking days; effect greater in smokers who reduced smoking. Effect increased over time - RCT 131 smokers with AUD: only reduced percent heavy drinking days in men - Side effects generally mild: nausea, abnormal dreams, constipation

Gabapentin for alcohol use disorder

Rationale: - Reduces neurotransmitter release by inhibition of calcium channels with α2δ-1 subunits - Reduces symptoms of alcohol withdrawal; improves sleep; mild cognitive effects - Renal excretion (safe if patient has liver disease) Limitations: Promising results in 2 of 3 trials - improved rates of abstinence, mood, sleep and craving; reduced no heavy drinking days compared with placebo - No effect on heavy drinking days or other drinking measures - reduced no heavy drinking days compared with placebo, mainly in group with high pretreatment alcohol withdrawal scores.

Varenicline for nicotine abuse

Rationale: - α4β2 receptor antagonists reduce nicotine intake but precipitate withdrawal - partial agonist of α4β2, α3β2, and α6 nicotinic cholinergic receptors - Decreases nicotine-induced DA release in nucleus accumbens - Reduces nicotine CPP, sensitization, reverses increases in ICSS thresholds during nicotine withdrawal, nicotine self-administration, nicotine and cue-induced reinstatement Clinical experience: - Reduces craving and withdrawal symptoms; reduces pleasurable effects from smoking and blood-oxygen-level-dependent (BOLD) fMRI responses to cigarette cues - Long half life (24h); 90% excreted in urine unchanged; no reported drug interactions - Side effects: nausea in 30%, insomnia initially, abnormal dreams and constipation in some. - As effective as combined NRT; adding NRT provides no benefit; more effective than bupropion

Methadone for opioid use disorder

Rationale: - Long acting oral opioid receptor agonist - Reduces withdrawal and craving - Long half-life - Can be used in a taper over 2-3 weeks for acute withdrawal - Effective for maintenance in patients at risk of relapse - Decrease mortality by 50% and rates of HIV and hepatitis, re-incarceration Limitations: - side effects: dose-related sedation, respiratory depression, prolonged QT interval - Diversion risk; offered only through approved clinics

Naltrexone for opioid use disorder

Rationale: - Synthesized in 1965 as a synthetic opioid- Antagonist at μ > κ >> δ receptors - Blocks acute effects of μ opioids and reduces effect of dynorphin during withdrawal - Oral and depot forms. Longer ½ life (4h) than naloxone (0.5-1.3h) Limitations: - Can provoke withdrawal; use only after complete detoxification - Works with highly motivated patients, maybe because lacks rewarding effects - Injectable depot form may be as effective as Suboxone in fully detoxified people. - No diversion risk - Adverse effects: hepatotoxicity, dysphoria, nausea, fatigue

Buprenorphine (Subutex, Suboxone) for opioid use disorder

Rationale: - μ-opioid receptor partial agonist, δ- and nociceptin receptor agonist, κ-opioid receptor antagonist - Reduces withdrawal and partially blocks intoxication - Sublingual, with effects lasting 24-36h - Less sedation and respiratory depression than methadone Limitations: - Can precipitate withdrawal; start low dose 12-18h after last dose of short acting opioid - Some diversion - Prescribed by physicians with special training; must offer counseling - Used as 4:1 ratio with naloxone for maintenance to discourage IV use.

Naltrexone for alcohol use disorder

Rationale: Antagonist at μ > κ >> δ receptors, Blocks euphoric effect of ethanol and reduces effect of dynorphin during withdrawal Limitations: Small effect size, Decreased return to drinking, Most effective in actively drinking individuals with family history and strong craving, Adverse effects: hepatotoxicity, dysphoria, nausea, fatigue.

Disulfiram for alcohol use disorder

Rationale: Blocks aldehyde dehydrogenase, Reduces drinking via fear of punishment in highly-motivated patients Limitations: Low strength of evidence overall, May cause liver toxicity, Disulfuram/ethanol reaction can be fatal

Acamprosate for alcohol use disorder

Rationale: May reduce NMDA and mGluR5 receptor signaling (???), Approved to sustain abstinence, Well tolerated and does not interact with psychotropics, Diarrhea is only major side effect; Not metabolized by liver Limitations: Small effect size, Decreased return to any drinking, Contraindicated in patients with severe renal impairment - effects may be caused by calcium in calcium acamprosate

Bupropion for nicotine abuse

Rationale: Reduces norepinephrine and dopamine reuptake (NDRI), Noncompetitive inhibitor of α3β4 and α4β2 nACh receptors, Reduces nicotine withdrawal and may attenuate reinforcing properties of nicotine, Approved to treat seasonal affective disorder, Metabolized by CYP2B6 to hydroxybupropion which is more active. Clinical experience: Produces abstinence rates of ~20%, increases quit rate 1.6-fold, Effects wane over time, May cause seizures and lower seizure threshold (depends on dose), Anecdotal reports of abuse (self administered by squirrel monkeys)

historical definitions of substance use

Recreational: occasional, controlled, or social use Drug Abuse: causes physical or mental harm Addiction: behavioral dependence Drug dependence: strong desire for drug resulting in damage to individuals or society

What are the well confirmed medical uses of cannabinoids?

Refractory neusea/vomiting anorexia/appetite loss HIV/AIDS/Cancer cachexia

PCP self administration

Reinforcing effects - Readily self-administered in animals to point of intoxication - Rats learned to lever press for accumbal injections of PCP, or two other NMDA receptor antagonists. - self-administration not blocked by coadministration of a dopamine receptor antagonist (sulpiride)

Describe the phases of opioid intoxication?

Rush (45s): intense pleasure or euphoria, rush is resistant to tolerance Nod (15-20 min): a state of escape from reality that can range from sleepiness to unconsciousness. Calm, detached, and uninterested. High(several hours): state that follows the rush and is marked by increased feeling of wellbeing, and shows tolerance Being straight (up to 8 hours):no longer experiencing high or rush but also not yet at the point of withdrawal.

What are the four major cannabis gene pools? What are their relations with CBD and THC?

Sativa - fiber/seed: low TCH, Med/high CBD - Marijuana: High TCH, low CBD - Hashish: High TCH, Med-low CBD Indica - Hashish: High TCH, high-low CBD

What are some general strains of cannabis?

Sativa, indica, ruderalis

Effects of repeated psychostimulant administration

Sensitization: psychomotor stimulant effects, stereotypy, craving, psychotomimetic effects (amphetamine psychosis) Tolerance: most autonomic effects, anorectic effects, euphoria, and subjective high

Describe the various roles of the endogenous opioid peptides

Sensory role: analgesic effects Modulatory role: gastrointestinal, endocrine, autonomic effects Emotional role: reward and addiction Cognitive: modulation of learning and memory - Prodynorphin -> dynorphin (pituitary/adrenal medulla) - Proopiomelanocortin -> endorphin (pituitary) - Proenkaphalin-> enkphalin (brain/ adrenal chromaffin cells)

Major effects of LSD

Sensory-Perceptual: pseudo hallucinations, illusions, synesthesia, etc. Psychic Experiences Somatic Effects: Dizziness, tremor, weakness, up to mydriasis, tachycardia, hypertension in overdose

site vs mechanism of drug action

Site: part of body organ, tissue, cell or protein target (receptor) where drug acts to start the chain of events leading to an effect. Mechanism: the means by which the presence of a drug produces an alteration in function. Often involves binding to receptors to produce an effect

How can cannabis impair motor performance?

Slowed reaction time, Poor detection of periphery, Space and time distortion, impaired coordination, accelerating/braking error, Poor speed control, Poor judgement

Sniffing vs huffing vs bagging

Sniffing: inhalation of vapours from an open container or heated pan. Huffing: oral inhalation of vapours by holding a piece of volatile-soaked cloth against the mouth. Bagging: inhalation of vapours from a paper or plastic bag.

What are the less well-confirmed uses of cannabinoids?

Spasticity due to spinal cord injury, Multiple sclerosis, Neurogenic pain, Movement disorders, Bronchodilation effects, glaucoma

Therapeutic index

T.I.=Toxic Dose 50/Effective Dose 50 TD50=dose at which half of max adverse effect is reached ED50=dose at which half of max therapeutic effect is reached - higher TI means safer drug

transcranial magnetic stimulation (TMS) for treatment of substance use disorder

TMS in PFC proved to be potential therapeutic for reducing cocaine use

Impulse control disorders

Tension/arousal -> impulsive acts -> pleasure/relief/gratification -> regret/guilt/self reproach -> back to tension/arousal involves positive reinforcement

Which metabolic pathway is typically used for drug testing? Why?

The 11-OH -> COOH is where most THC goes so it is used in drug testing

therapeutic and side effects of benzodiazepine site ligands

Therapeutic: calming and relaxation Side effects: motor incoordination, intoxication (like alcohol), amnesia, sedation & sleep, coma, and respiratory depression

Acute Functional Tolerance

This is a form of tolerance observed within the time frame of a single exposure to the drug. - Animals were then trained to balance on wooden dowel. - During the testing period, all subjects received ethanol, and then were placed on the dowel. - When the subject lost its ability to balance on the dowel, the time was recorded and BEC measured. - The animals were then placed on the dowel every 5 min thereafter until they regained the ability to balance on the dowel for 1 min. - Once this criterion was met, the time and BEC recorded. The BEC of this sample was labeled T1 and used in calculating the rate of acquisition of functional tolerance. - The subject received an intraperitoneal injection of ethanol. The subject was then repeatedly placed on the dowel until it again regained the ability to balance for 1 min on the dowel. When this criterion was achieved, the time and BEC was recorded

Describe the methods and results of the experiment relating to precipitated cannabinoid withdrawal?

Time course of effects of CBI receptor inverse agonist on dopamine release in nucleus accumbens - measured % baseline dopamine vs time after rimonibant administration in rats given 1 and 5 mg/kg - greater doses decreased dopamine levels to a greater extent

which three disorders have FDA-approved medications?

Tobacco, Opioids, Alcohol

Medications for Tobacco and Opioid Use Disorders

Tobacco: Nicotine replacement, Bupropion, Varenicline Opioids: Methadone, Buprenorphine, Naltrexone

Off-label medications for Alcohol Use Disorder

Topiramate, Varenicline, Gabapentin, Baclofen

Analyzing the Transcriptome

Transcriptome: the set of all RNA produced in a cell, mRNA transcripts reflect which genes are actively expressed and gene expression controls cell structure and function - Transcriptome responds to genetic variation and environmental conditions Technically accessible through: Microarray, RNA sequencing

operant conditioning in animal models

Type of learning involves a procedure whereby the probability of the occurrence of a particular behavior can be either increased or decreased, depending on the consequences of that behavior. Eg: Lever press: operant response (animal operates on its environment to change it in a meaningful way). Food pellet or drug: positive reinforcer (strengthens the behaviour that resulted in its presentation).

spray tan addiction

UV seeking behavior has addictive features - induces beta endorphin levels, elicits withdrawal after chronic UV exposure

What are some symptoms of cannabis use disorder?

Use despite problems, Intoxication, Much time getting/using/recovering, Withdrawal symptoms, Foregone social/occupational activities

side effects of cocaine use

Vasoconstriction (necrosis, ulceration), Local anesthetic (Na+ channel blocker), cerebral hemorrhage, and cerebral ischemic stroke

Describe the therapeutic uses for CB1 receptor antagonists and inverse agonist?

Weight loss, smoking cessation, and alcohol use disorder - Rimonabant (inverse agonist) approved in Europe in 2006 for obesity, but discontinued in 2008 because of side effects (depression, anxiety, nausea).

is THC reinforcing? If so, describe the experiment that demonstrated this?

Yes, Dose-response curves for IV self administration showed increase in response or self stimulation as dose of THC increased, however, began to decrease again toward the higher doses

Zero vs First order kinetics

Zero order: constant amount per unit time first order: constant fraction per unit time (has a half life) - half life is the time it takes to reduce the concentration by 50%

microsatellite

a region of dinucleotide repeats

describe effects of cannabinoids on presynaptic cells

act by second messenger pathways to enhance potassium channels and inhibit Ca2+ channels as well as sodium channels to inhibit presynaptic cell - endogenous cannabinoids often released from post synaptic cells

Stages of addiction

acute reinforcement/social drug taking -> Escalating/impulsive use -> Dependance -> withdrawal -> Protracted withdrawal (or relapse) -> Recovery stages influenced by: genetic variables, environmental factors, stress, and conditioning effects

possibilities effects of drug-drug interactions

additive (1+1=2) synergism (1+1=3) Potentiation (1+0=2) Nothing (1+1=1) Antagonism (1+1=0)

Common inhalants

airplane glue, butane, acetone, scotchgard, paint thinner, gasoline, cleaning supplies, paint Commonly abused inhalant compounds: toluene, trichloroethane, trichloroethylene, xylene and hexane. - Inhalant abuse often takes the form of long-term, high-concentration exposure.

which drug has the greatest overall harm score

alcohol

what is the most common type of substance use disorder

alcohol use disorder

features of nicotine withdrawal

anxiety, difficulty concentrating, irritability, restlessness, awakening at night, hunger, weight increase (?), heart rate, craving, depression

Compulsive Disorders

anxiety/stress -> repetitive behaviors -> Relief from stress/anxiety -> obsessions -> back to anxiety/stress - involves negative reinforcement

methods of drug classification

based on effect, mechanism of action, or chemical structure

allosteric modulators

bind to a site on the receptor distinct from that of the agonist and affect receptor function. They have no effects in the absence of agonist. can have several different effects 1. decrease agonist EC50 without affecting max response 2. increase agonist EC50 without affecting max response

animals working for nicotine

breaking point of FR responding vs dose in dogs for cocaine and nicotine - showed animals will work for nicotine

health consequences of smoking

cancers: larynx, esophagus, lung, liver, colorectal, stomach, etc. chronic diseases: diabetes, birth defects, coronary heart disease, stroke, etc.

types of drug names

chemical, non proprietary (generic), proprietary (trade), and common names

Heritability of addictive disorders

cocaine has the greatest heritability heritability is generally positively correlated with risk of addiction

what factors increase alcohol absorption

consuming alcohol on an empty stomach, age, and gender

Tolerance

decreased response to the same dose of drug over time, or requiring a higher dose of the drug to elicit the same effect as found previously

factors governing extent of drug use

degree of social acceptance, social upheaval (ex. heroin epidemic among Vietnam soldiers), legal controls, price, ease of availability, occupational factors

Content validity

does it assess all facets of the human model that you are trying to model?

predictive validity

does it predict the success of certain therapeutics in humans?

factors affecting passive transport of drugs

drug concentration gradient across cell membrane, degree of ionization and drug polarity, cell membrane surface area, binding to proteins Pm/b = Coil/Cwater

Rosetta Stone Approach

dynamic feedback between animal models and clinical data in order to identify treatments that are more likely to be successful in clinical trials

The binge cycle (Cocaine)

euphoria <-> dysphoria -> paranoia -> psychosis Euphoria: Increased affective lability, increased motor & cognitive performance, hyperactivity, hyperalertness dysphoria: Melancholy, apathy, difficulty concentrating, insomnia paranoia: Suspiciousness, persecutory paranoia, grandiosity, hallucinations psychosis: Paranoid delusions, hallucinations, anhedonia, stereotypy, disorientation - This cycle can be observed in individuals smoking a single high dose of cocaine or those who exhibit low-dose chronic patterns of use. - The faster the onset of drug effect (pharmacokinetics) the more intense the euphoria and the more quickly dysphoria then sets in. - dysphoria seen while drug plasma levels are still high - not due to a pharmacokinetic effect - as cocaine use increases, positive reinforcing effects decrease while dysphoria increases

imprinting

gene expression depends on parental transmission

progressive ratio method

gradual increase of response requirements (number of responses required to receive a reward) and investigate the number of responses that the animal is willing to do without reward, or their break point (?)

which substance has the greatest rate of addiction development in users

heroin

homopentameric vs heteropentameric receptors

homopentameric: receptor made up of a single type of subunit (Ex: a9, a10, and a7) Heteropentameric: made up different subunits

selective breeding

identify individuals with phenotype of interest and breed those animals

nicotine poisoning

incidences have increased since the development of e-cigarettes but can also be developed by eating cigarettes most significant symptoms include nausea and vomiting

process of drug dependence and withdrawal

initial state -> drug state -> tolerant state (opposing neuroadaptation) -> withdrawal state (neuro adaptation exposed upon removal of drug) -> dependent state (drug is required to restore balance)

chemical characteristics of ethanol

low binding energy - hydrogen bonding at OH group - very weak hydrophobic interactions - low affinity interactions with proteins consistent with in vivo potency 10-100 mM

opioid dependance/withdrawal on stress response

measured corticosterone vs time in nondependent, morphine dependent, 12 hr withdrawal, 8 day withdrawal, and 15 day withdrawal - measured in rats undergoing no restraint, 15 min restraint, and 4 hour restraint - shows dysregulation of HPA axis - also increases levels of stress hormones such as dynorphin in extended amygdala

classifications of drug origins

naturally occurring, pure compounds, semi-synthetic, and synthetic

Compare and contrast opium, opiates, and opioids

opium= yummy poppy juice opiate= any agent derived from opium (or looks like opium) - subclass of opioids opioid= all substances with opium like properties/bind to opioid receptors Essentially: All opiates are opioids but not all opioids are opiates

significance of surgeon generals report in 1964

outlined negative health consequences of smoking and caused significant reduction in smoking

endophenotype

particular characteristic related to a given phenotype

methods of transcellular passage of drugs

passive transport, active transport, pinocytosis, and facilitated diffusion

ED50 values (μmol/kg) plotted against the KI (nM) value for 29 different cannabinoids for binding at the CB1 receptor

plotted ED50 vs binding affinity for different behaviors

relationship between prenatal alcohol exposure and brain size

prenatal exposure to alcohol and fetal alcohol exposure are associated with reduction in brain size in both cerebrum and cerebellum

relationship between prenatal alcohol exposure and intelligence

prenatal exposure to alcohol and fetal alcohol exposure are associated with reduction in general intelligence and executive functioning

what are socially acceptable uses for psychoactive drugs

religious ceremonies (ex. using peyote to talk with the gods), secular ceremonies (ex. passing a joint at a party), private pleasure, and business

Schedule classifications of drugs

schedule 1: no accepted medical use and high abuse potential Schedule 2: recognized medial use but high abuse potential Schedule 3: recognized medical use but lower abuse potential than 2 Schedule 4: medical use but lower abuse potential than 3 Schedule 5: medical use but lowest abuse potential

Genomics

studies of the structure, function, evolution, mapping, and editing of "genomes" (an organism's complete set of DNA, including all of its genes)

direct vs indirect sympathomimetics

sympathomimetics are compounds that mimic norepinephrine direct sympathomimetics bind directly to receptors (Ex. dopamine, epinephrine, norepinephrine, isoproterenol, and phenylephrine) indirect sympathomimetics do not bind directly to receptors (ex. cocaine, methamphetamine, amphetamine, buproprion (NDRI), and reboxetine (NRI)) non sympathomimetics (Ex. caffeine, nicotine, scopolamine, and strychnine)

linkage

the association of genes on the same chromosome. Also, the association of a gene with a trait.

epistasis

the masking of one gene by another

Transcriptomics

the study of the transcriptome—the complete set of RNA transcripts that are produced by the genome, under specific circumstances or in a specific cell

Heritability of addiction is measured using

twin studies, linkage studies, candidate gene studies, genome-wide association studies (GWAS), and animal models

conditioned place preference

two different unconditioned stimuli (e.g. drug vs saline) are repeatedly paired with two distinct environments and measure time spent in each environment to determine preference EX: morphine increases preference for specific environment and ketamine blocks morphine induced CPP

Therapeutic uses of amphetamines

weight control (methamphetamine), ADHD, Alertness, awakening(used by US military), Narcolepsy

Rebound insomnia

when administered triazolam, measured total time awake vs night. measured on nights 2-4 (baseline), 5-7 (drug), 16-18 (drug), and 19-21 (withdrawal). - during withdrawal, patients experienced greater levels of sleeplessness