BBH 451 Test 3
Amphetamine primarily increases the intracellular concentration of dopamine by:
Acting on VMAT - It reverses the action VMAT, which increases dopamine in the cytoplasm
LSD history
Albert Hoffman: synthesis in 1938 and accidental (?) trip (1943) Tim Leary - harvard professor, experiments with psilocybin and LSD - Dismissed from Harvard in 1953 (LSD not illegal until 1966) Central intelligence agency MK-ULTRA (MIND CONTROL PRJECT) - thought they could get people to open-up and tell secrets - shut down bc people would kill themselves
History of MDMA (Ectasy)
3,4 - Methylenedioxymethamphetamine - Developed in Germany in early 1900's along with other psychotropic drugs - Used in US 60's and 70's as psychotherapeutic drug - Not FDA approved, but not illegal either - Early use was self-limiting, generally - Popular as street drug in 1980's -- only illegal after 1985 (Schedule 1) - Finally popular as a "club drug" at raves - Increasing use on college campuses and in younger adolescents
Mescaline (Peyote)
(might) Treat substance abuse (phase 1 trials) -intoxication lasts 8-10 hrs -grows naturally in SW texas, mexico - religious use in north america including navajo - religius freedom restoration act (RFRA)
History of cocaine
- 1800's: additive in wine and soft drinks - possible subject in literature - restricted use in early 1900's - Pure Food and Drug Act - Increase in use in 70's&80's (crack epidemic)
Therapeutically useful pharmacological effects of amphetamine
- Adderall is (d/I) amphetamine (racemic mixture) - Dexedrine is (d) dextroamphetamine - Narcolepsy - sleep disorder, sudden sleep attacks and muscle weakness -ADHD - Obesity - Abuse of related compounds
Effects of amphetamine on VMAT
- During early stages of amphetamine stimulation, dopamine levels in the cytoplasm are very low - During early stages of amphetamine stimulation, amphetamine is taken into the neuron by the dopamine transporter - During late stages of amphetamine stimulation, dopamine flows backwards out of the neuron through the dopamine transporter (Not true: During middle stages of amphetamine stimulation, dopamine concentrations in vesicles is very high)
MDMA Pharmacokinetics
- Effects apparent within 1 hour of taking pill - Metabolite MDA (methylene-dioxy-amphetamine) is probably more potent than MDMA
Positive psychological effects of MDMA
- Feelings of empathy - Friendliness - Sense of well being - Extreme decreases in fatigue - Hallucinogenic effects (not always positive - some are fearful) - Heightened perceptions - Crossed sensory perceptions (synesthesia)
Chronic effects of meth
- Heart complications - Neurotoxin: reduction in grey matter, degenerates midbrain dopamine neurons, may increase risk of parkinsons-like disease, blood brain barrier disruption - Severe addiction: long-term effects of addiction (anhedonia - no pleasure, hypofrontality - low level from frontal cortex) are especially severe - There are also gruesome phyiscal changes
Peripheral effects of amphetamine resemble activation of the sympathetic nervous system, in particular to release of Epinephrine (Adrenaline):
- Increased blood pressure - vasoconstriction - dilated pupils - increased blood flow to muscles away from internal organs and skin - Blood glucose levels rise
MDMA Pharmacology
- Increased serotonin level in synapses. Blocking reuptake and stimulating reverse transport - Action on 5-HT2A receptors in particular - NE and DA levels increase as well (considered a psychomotor stimulant) Increase serotonin, 5-HT2A receptors, NE and DA increase
Early period of cocaine
- Indigenous south american use - initial medical uses of this alkaloid in western cultures as potent local anesthetic - sigmund freud's prescription - cocaine's stimulant effects became known quickly
Potential problems with the monoamine hypothesis as related to serotonin?
- Many people have low basal serotonin levels, yet they don't have depression - Experimentally decreasing the amounts of serotonin does not result in depression - Treatments that do not target serotonin work just as well as those that do target serotonin
Phantasticum
- Milder alteration in sensory perception - Invented to promote drugs to enhance perception, expand reality, promote personal awareness, and comprehend the spiritual or supernatural
Deliriant's (Psychotomimetic) drug category
- Mimics psychoses: delirium/delusions - Generate a state of violent mental agitation, marked by uncontrolled excitement or emotion, a condition of severe confusion (severe fever) - Can become violent - Non-nicotenic
Dissociative drug category
- Mixed perception, seperation from the body - Diminished signals that convey one's physical senses (the body is separated from the mind) - Feels like they are standing outside of their body (LSD, PCP, Ketamine)
Drug categories
- Psychedelic - Hallucinogen - Deliriant's (Psychotomimetic) - Dissociative - Phantasticum
Ergot of Rye
- Salem witch trial: ergot poisoning (ergotism): convulsive seizures, twisting and painful contortions, blashemous screaming, and trance-like states - Another form of ergotism causes gangrene, but not sen in salem - 20 people died by being accused of witchcraft - Rye cultivated as food starting in the early middle ages (400-500 AD) mainly in Russia, France, and Germant (Ergotism: Holy fire, later St. Anthony's fire) - Dr. Tuillier, French physician, proposed consumption of contaminated rye was the cause in 1670
DEA Schedule of drugs
- Schedule 1: no medical use (heroin, ecstasy, marijuana) - Schedule 2: medical use but highly addictive (morphine, oxycodone, Ritaline, cocaine - all forms, including crack) - Schedule 3: medial use but less addictive [Alprazolam (Xanax), Tylenol 3]
Synthesia Ex
- Sound felt physical - Strong memory - remembered everything - Even with remembering everything this patient was not that successful in life - Descriptive examples: #1 was a "proud, well-built, man", #2 was a "high-spirited woman", #6 was a "person with a swollen foot"
Why is meth more potent?
- more lipophilic (get into brain easier) - Increases tyrosine hydroxylase levels (leads to more dopamine synthesis) Cocaine blocks reuptake
Vesicular monoamine transporter (VMAT2)
1. packs vesicles with manoamine (dopamine, norepinephrine) 2. requires energy (ATP) 3. Antiport for H+ (pH dependent) 4. The H+ in the vesicle came from a proton pump that puts H+ in the vesicle, which makes the vesicle acidic
History of amphetamine
1887 - chmically synthesized (not natural) from ephedrine Benxedrine - 1928 WW2 for alertness No perscribed for selected problems
Metabolism of meth
20% of meth is excreted unmetabolized, some is metabolized by CYO2D6 to parahydroxy-methamphetamine - Amphetamine, which is also generated by CYP2D6 - Able to remove methyl group and make amphetamine - Extends time to when drug can be active
Treatments for cocaine dependency
Anti-epilleptic medications Cognitive behavioral therapy Tricyclic anti-depression medications Disulifram Cannabinoid antagonist Methylphenidate Cocaine vaccine (IM)
MDMA + Cannabis
Attenuation of MDMA-induced hyperthermia; memory deficit lowered hyperthermia
•Given the pharmacokinetics of Ecstasy, is Ecstasy a drug or a prodrug? (Remember definition from Pharmacogenetics lecture.)
Both drug and prodrug
In the neurogenesis hypothesis of depression, what protein directly increases transcription of Brain Derived Neurotrophic Factor gene, and therefore its protein?
CREB
sympathomimetic substances
Caffeine, cocaine, nicotine Glutamate is not one
Hallucinogen drug category
Causes hallucination -- unreal experience in which there is no awareness of lack of reality (Can't tell what is real)
Psychedelic drug category
Causes unreal experience in which user is aware of lack of reality -- not hallucinating (LSD)
LSD effects
Changes in sesory experiences includingL synthesia, visual illusions and hallucinations, enhanced awareness of external stimuli Psychotomimetic: experience mimics a state of psychosis, produce rapid tolerance, flashbacks, neuronal death Low addiction liability
Cocaine forms
Coca leaf: chewed, slow release, no euphroia, addiction unclear Higher dose - all day 200mg Cocaine hydrochloride salt (HCI): paste from leaves (pure drug), soluble in water (easy for use), euphoria, normally snorted or injects, but not smoked Shorter time period 100-150 mg
Cocaethylene
Cocaine and alcohol Increases half-life
Bufotenin
Comes from frog skin DMT - FOund in hgiher concentrations in schizophrenics than controls (might be synthesized by the pineal gland) - Might act through trace amine-associated receptros - which are GPCR's activated by phentylethylamine, tryamine, tryptamine and other rare animes - added to artificial versions of ayahuasea -preclinical trials are underway for mood disorders
What are the cardiovascular effects of using methamphetamine?
Constriction of blood vessels, increased blood pressure and increased risk of heart attack
Dopamine without cocaine
DA is released tonically -Continual activation of DA receptors. Normal consequence of reuptake -Metabolism by MAO (~30%) -Repackaging in vesicles (70%)
What does Amphetamine stimulate the release of?
DA, NE, and EPI, which results in high DA release
Amphatamine pharacodynamics
DAT selective pore that is largely (not completely) passive. (Ligand follows its concentration gradiant, Na+ is co-transported and it follows its gradient as well) VMAT2 is an active pump (works against the concentration gradient) in neurons that use monoamines. What controls the (DA) in synaptic cleft, cytoplasm, and vesicles
Positive effects of amphetamine
Elevated mood Increase motor activity (Paradoxical b/c used to treat ADHD) Increase in alertness - WW2 Decrease need for sleep -WW2 Increase metabolic activity (brain and body) mostly via #2
Is LSD pure or synthesized?
Entirely synthetic
Structures of the compounds
Ephedrine is similar in physical structure - has more psychological effects (appetite and decongestion) Pseudoephedrine - runny nose Amphetamine mimics dopamine
LSD pharmacodynamics
Extremely potent (Hoffman's first intentional dose of 250 micrograms was 10X than needed) Agonist for 5-HT2A receptor
Clinical trials of MDMA for PTSD
FDA listed MDMA as schedule 1 (1985) to push for legal medical use - 2017: breakthrough therapy (based on analysis of 6 phase 2 trials) - Contention is that MDMA works better than Sertraline and Paraoxetine (2 SSRI's) and trauma-focused psychotherapies (e.g. eye movement desensitization, cognitive processing therapy, prolonged exposure) - MDMA-assisted psychotherapy phase 3 trials started in Nov. 2018, a last step before possible prescriptions use in PTSD patients
THC can last a long time in the body, and is primarily stored in:
Fat
Freebase and crack
Freebase: add ammonia and dissolve cocaine in ether to leave HCL behind in water Crack: add ammonia or sodium bicarbonate, and heat to evaporate HCL (cracking noise) More effective, but long-tem difference in addictiveness is small
When LSD was first discovered in 1942 by Albert Hoffman, his experience was abnormally intense. What may have caused this?
He took a significantly larger does than was recognized later
Cocaine has two isomers; (+) and (-). If you need more of the (+) isomer than the (-) isomer to block dopamine uptake, would the Kd of (+) Cocaine be higher, lower or the same as (-) Cocaine?
Higher We need more (+) to get reaction
MDMA increases levels of serotonin and can lead to a Serotonin Syndrome. Which of the following is not a symptom of Serotonin Syndrome?
Hypothermia
Negative effects of amphetamine
Inability and withdrawal-induced depression Anorexia Anxiety and paranoia Insomnia Psychosis and aggression at high doses Compulsive, repetitive behavior - stereotype
Psychological effects
Increased alertness Immediate euphoria Giddiness Enhanced self-consciousness Forceful boastfulness Decreased appetite Become very talkative and incoherent
Regarding the effects of depression on the hippocampus, which possible symptoms of depression related to the hippocampus?
Increased anxiety Inability to express feelings Memory deficits
What is the primary mechanism of action of cocaine?
Inhibits the reuptake of dopamine, serotonin and norepinephrine
Side effects of SSRIs
Insomnia Sexual Dysfunction Nausea
A natural ligand (neurotransmitter) causes sodium leak channels to open, allowing more sodium to pass through than the small amount that occurs without neurotransmitter binding. A drug causes these sodium channels to close entirely. What could the drug be classified as?
Inverse agonist Represents an antagonist-like activity, but more severe
What is the primary effect of amphetamine?
It reverses the action of VMAT, which increases dopamine in the cytoplasm
Vicks vapor rub
L-form (levmethamphetamine)
The action of several drugs has provided insight to the neurophysiology of schizophrenia. The relevant drugs are:
LSD and PCP
Serotonin syndrome
Life threatening drug reaction - Excess serotonin activity - cognitive effects: headache, agitation, metnal confusion, hallucination, coma - Autonomic effects: shivering, sweating, hyperthermia, hypertension, tachycardia - Somatic effects: myoclonus (muscle twitching), tremor
Which form of amphetamine is a prodrug?
Lisdexamphetamine
Psychedelics that are catecholamine-like
MDMA Nutmeg Mescaline
Does meth or amphetamine have a longer half-life
Meth (12 hr)
History of meth
Methadrine (Pervitin in Germany) - Synthesized in 1893 but no value recognized - Used by soldiers in WW2 - Postwar surplus caused epidemic in Japan, popular in US by 1960s then declined in 70s -Regulated by controlled substances act in 1970 (can be perscribed for ADHD and obesity - Desoxyn) - Popularity rose drmatically starting in Hawaii in late 80's when high school kids realized it could be smoked. Spread to rural areas of USA in 90's
Physiological effects of cocaine
Musculature Heart - collapse Blood vessels Lungs Body temperature (sympathomimetic)
Which drug has been prescribed with a standing order to prevent opioid overdose deaths?
Naloxone
Use of marijuana results in increased synaptic dopamine in which area (choose the one with the largest change)?
Nucleus accumbens
Administration for meth
Oral Intranasal Inhalation Injection
How is cocaine absorbed
Oral Intranasal (snorting) Inhalation (smoking) Intravenous (shooting up)
A natural ligand (neurotransmitter) causes sodium leak channels to open, allowing more sodium to pass through than the small amount that occurs without neurotransmitter binding. A drug causes these sodium channels to open to a level greater than when no neurotransmitter is present but not as high as when the neurotransmitter is present. What could the drug be classified as?
Partial agonist Works at partial extent, but not fully
Serotonin-like actions (chemical classification of psychedelic drugs)
Physiological similarities - LSD (Lysergic acid diethylamide) - Psilocybin (mushrooms) - Bufotenine
Psilocybin (mushrooms)
Prodrug; has to be chemically modified by body intoxication lasts 3-4 hrs grows in temperate climates religious use in mexico treatment for depression
MDMA + EtOH (ethynol)
Prolonged feeling of euphoria and feeling of well being; no additional effects on executive function, memory, psychomotor and attention function
What ingredient is found in a common cold medication and is also a precursor to methamphetamine?
Pseudoephedrine
Structural similarity of meth to other drugs
Pseudophedrine, methamphetamine --> meth (often leads to fires and explosion) Two isomers: I- and d-methamphetamine L-methamphetamine used in OTC nasal decongestants D-methamphetamine used in the abused isomer (S form is also D)
What psychedelic is not catecholamine-like?
Psilocybin
This type of drug produces an experience where the user is aware that what they are experiencing is not reality
Psychedelic
Negative effects of MDMA
Psychological: - anxiety/agitation - impulsivity and loss of self-control - paranoria - depression-like state Physical: - hyperthermia -- unable to effectively regulate body temp - nausea = seizures -dehydration -hypertension
LSD pharmacokinetics
Rapid uptake by the brain Effects begin 20-90 min., usually lasts between 4-12 hr (contaminants, environment - including flashbacks with no drug)
MDMA + caffeine
Reduced drowsiness and fatigue
Addiction to methamphetamine often causes anhedonia, which can be described as
Reduced interest in pleasurable activities
MDMA and usage
Self-limiting: use only once - Doesn't change perception, but gives a different view
What does ecstasy increase?
Serotonin norepinephrine Dopamine
Monoamine Oxidase Inhibitors (MAOI's) act on which of the following neurotransmitter pathways?
Serotonin and norepinephrine
MDMA + Meth/Amph
Severe long term cognitive, behavioral and neurological changes; increased neurotoxicity (increased risk for serotonin syndrome)
How does the half life of amphetamine compare to methamphetamine and cocaine?
Shorter than methamphetamine, but longer than cocaine
What effects would you expect amphetamine to have?
Similar to cocaine, but faster and a little more intense
R-form of meth
Similar, but faster and more potent than amphetamine - Primary action: dopamine release from vesicles that are inside presynaptic dopamine neurons - Psychological activity and sympathomimetic
Catecholamine-like actions (chemical classification of psychedelic drugs)
Some have structural similarity - MDMA (Ecstasy) - Myristicin, elemencin (nutmeg & mace) - Mescaline
A drug that mimics a response from the sympathetic nervous system is said to be a ____.
Sympathomimetic
Stacking
Taking 2nd or 3rd dose before 1st dissipates - severe hyperthermia, hypertension - arrhythmia - kidney failure - these symptoms cluster into something known as serotonin sydnrome
What common action do all antidepressants have?
They increase concentrations of norepinephrine and/or serotonin. Dopamine might be involved, but not central.
In what case do antidepressants clearly out-perform placebos?
Those with severe depression
How does smoking tobacco influence the half life of caffeine?
Tobacco increases the activity of CYP1A2, decreasing the caffeine's half life Smokers have to drink more coffee for the effect compared to nonsmokers. Important for smokers to lower coffee/caffeine intake when quitting smoking for this reason.
Pain relief by drugs can occur at several sites. At the site of injury the relief comes from blocking _____________, which is the primary action of NSAIDS. The signaling from the site of injury can be blocked by _____________ the sodium channels, which is an action of __________. The most common class of drugs for severe pain, the _____________ work in the CNS on a different type of receptor, the ______ receptor, whose ________________ ligands are enkephalin and beta-endorphin.
inflammation/prostaglandin synthesis antagonizing cocaine opioids/opiates Mu/ mu-opioid receptor Endogenous/native/natural
Is cocaine good at blocking dopamine?
no
Routes of administration for amphetamines
oral Intranasal Intravenous Metabolized by CYP2D6 Half-life 9-11 hours
4 actions of amphetamine
very minor - agonist at dopamine receptors because it is similar in structure to dopamine moderate - dopamine reuptake blockade. Amphetamine is transported into neuron via DAT, NET, & SERT transporters major- dopamine release. Amphetamine reverses action of vesicular monamine transporter 2 (VMAT-2). DAT transporters (passive) begin allowing reverse flow, allowing excess neurotransmitter into the synapse extremely minor - blocks MAO's at high conc., further increasing intracellular monoamine levels (not discussed further)
Dopamine action with cocaine
•Cocaine blocks reuptake -[DA] in synapse increases -DA receptor activity increases - •Action primarily in the Nucleus Accumbens (NAcc) •Euphoria is due primarily to this activation of DA receptors (indirect) •Cocaine is a competitive antagonist at the DAT -Seeming contradiction: Cocaine causes decreased firing of DA neurons -DA levels drop because of decreased firing, but only a little due to blockade of the DAT •DA release after learning the association of cocaine use and reward
Dopamine reuptake blockade
•Increasing [competitive antagonist (reuptake blocker)] diminishes the uptake of DA •Ability of Various Compounds to Block DA uptake in frog eggs is correlated with their ability in the rat nucleus accumbens •This activity of the two forms of cocaine leads to...
