PSY 313 Exam 3

Kappa agonists

(dynorphin) reduce dopaminergic activity -kappa activation of presynaptic VTA dopamine terminals reduces dopamine release in the NAC -kappa activation is aversive and not addictive -decreasing kappa receptor activity may reduce depression and pain -kappa activation involved in withdrawal. specifically in the unpleasant emotions with withdrawal

Fentanyl

-80-500 times as potent as morphine(heroin is 3 times as potent as morphine) -profoundly depresses respiration-more than morphine and heroin -often cut/mixed with heroin without the users knowing, making it ever more dangerous

Dopamine receptor antagonist

-PD, dopamine neurons fail to synthesize enough dopamine, solution is stimulate post synaptic dopamine receptors in basal ganglia and does not depend on neurons to synthesize dopamine

Bipolar disorder treatment

-anti-depressants discussed are used but other drugs are also used to treat the mania -lithium carbonate is the most effective medication, eliminates or reduces manic episodes without causing depression or producing sedation, particularly effective in reducing suicide in bipolar people

Valproate(Depakote)

-anticonvulsant to treat acute mania -probably alters calcium release and increasing brain levels of GABA -teratogenic: disrupts development of fetus -can cause autism in children of mothers who take it during the first trimester

Second generate antiphyscotics(SGA)

-atypical antipsychotics -block D2 receptors but also blocks serotonin receptors 5HT1a and 5HT2a -treat positive and negative symptoms -less likely to produce motor neurological side effects -effective as FGAs for schizo and other treatments -can have serious and life threatening side effects

Early life traumas

-can trigger permanent change in the hormonal response -can alter the set point for the HPA axis, making it permanently over responsive and increasing risk for later depression, anxiety disorders, and alcohol abuse -rats subjected to early life trauma showed high stressed induced ACTH and cortisol increased CRF in the brain, and a permanent increase in CRF gene expression as adults (epigenetics) -new approach is traditional antidepressants target monoamines(DA, NA, 5-HT)

AChE Inhibitors

-cause there to be more Ach to be present in the brain because they inhibit the enzyme that removes the Ach -side effects are because these drugs affect the entire body so the inhibition in the periphery are causing side effects to occur -drugs only provide some modest improvements and sometimes they dont outweigh their side effects

Senile plaques

-composed of amyloid beta protein -formed when the amyloid precursor protein is snipped at the wrong location -snipped fragments are not soluble -amyloid beta then clumps together to form these uncontrollable growing plaques -does not correspond with the symptoms of the disease -starts out in the cortex, then goes to the hippocampus then the rest of the brain

Neurofibrillary tangles

-composed of tau protein; holds microtubules together -formed when tau breaks away from the microtubules and clump together -these protein then clump together in the neuron thus degrading and killing the neuron -correspond with the symptoms of the disease -begins in the hippocampus and spreads outwards

Neurotrophic hypothesis of depression

-connection between BDNF and depression resulted in a hypothesis: depression reduced BDNF and reduce neural connectivity -Mechanism: antidepressants increase NE and 5-HT which raises BDNF which causes a slow recovery of dendritic branching and survival of neurons -Upshot: antidepressasnts prevent stress-induced reduction in BDNF and neuronal

Cannabis and Schizophrenia

-correlation evidence linking heavy use -general concern is that schizophrenic may take cannabis to self medicate but more recent evidence suggests that its more than this

Synaptic pruning and schizophrenia

-critiacal for normal brain development but may be distroted in schizo -excesive prining in the teens and beyond microglia may become too agressive , alters and reduces connectivity between brain regions -if pruning doesnt stop, it could explain why symptoms only emerge when male patient is in their 20s, could refelct when the over active pruning reaches its peak and produces symptoms

Depression, Circadian rhythms, and sleep

-depressed individuals have a more irregular circadian response to hormone levels -onset of sleep is delayed, and REM periods get shorter rather than longer as the night goes on -depressed individuals show a shorter REM latency at all stages. Means REM starts earlier in the night -for some depressed patients, sleep restriction is helpful. For others, it can trigger a manic episode -Melatonin has been used to resynchroniz circadian rhythms and sleep cycles, but it has a hsort half-life and it not very effective in sleep disorders in depressed pations -melatonin is produced by the pineal gland in the brain

How do opioids reduce pain signals

-descending midbrain pathways that act on the spinal cord, top down inhibition from the midbrain: PAG -final targets in the brain and ACC

treatment for parkinsons

-dopamine replacement therapies -deep brain stimulation -transplantation of dopamine stem cells in the brain of a PD patient

To be diagnosed with MDD

-either depressed mood most of the day nearly everyday for 2 weeks or diminished interest or pleasure in activities most of the day nearly everyday for 2 weeks -four or more of significant weight loss when not dieting or weight gain or decrease or increase in appetite nearly every day 2. slowing down of thought and reduction of physical movement 3. fatigue or loss of energy nearly every day 4. feelings of worthlessness or excessive or inapppropriate guilt nearly every day 5. diminished ability to think or concentrate or indesciveness 6. recurrent thoughts of death or suicidal ideation

Stress, MDD, and the hippocampus

-elevated cortisol also contributes to hippocampus damage -hippocampus neurons show reduced dendritic branches and spines after stress -reduced neurogenesis -degeneration: reduction in hippocampus volume, neurons dying -antidepressant drugs can reverse this in animal models of depression -antidepressants reduce CRF, reverse loss of dendrites, and increase neurogenesis in hippocampus

Anatomy in schizophrenia

-enlarged ventricles, show cerebral atrophy and enlargement of fluid-filled ventricles following cell or synapse loss(too much pruning) -Hippocampal cells of patients with schizophrenia are more disprganized than those of healthy subjects

Clozapine(Clozaril)

-first SGA -developed in the late 1950s D2 + 5HT1a and 5HT2a receptor blockade -lacks extrapyramidal motor side effects associated with traditional neuroleptics -reduces mortality rates and suicides -clinically superior to typical and other atypical antipsychotics -effective in 1/3 of medication resistant patients

MAOIs

-first generation -inhibition of MAO: result: less dopamine, NE, 5-HT broken down in the pre-synaptic terminal so more is released

Twin studies in depression

-if one monozygotic twin has a mood disorder, 65% the other twin does too -dizygotic rate is 20% -genetic concordance for bipolar is 80% -most individuals with depression do not have clear genetic link

Dopamine Imbalance hypothesis schizo

-imbalance in dopamine in prefrontal and striatum REDUCED dopamine in mesocortical areas (e.g., less dopamine in the prefrontal cortex Low PFC dopamine may produce the negative symptoms and cognitive symptoms INCREASED dopamine in mesolimbic areas (e.g., more dopamine in the nucleus accumbens) This causes positive symptoms and you see increased dopamine in NAC

2 stages to dependence

-impulsive: stage: motivation=positive reinforcing effects of the drug -compulsive(habitual) stage motivation: negative reinforcement(relief) from withdrawal -cycles of abstinence and withdrawal enhance classical conditioning to stimuli associated with the environments in which withdrawal occurs -withdrawal symptoms such as craving can then be triggered by exposure to conditioned stimuli

Descending control in spinal cord

-inhibit projection neurons directly -inhibit intermediate excitatory neuron -excite opioid neurons in spinal cord

Role neurotrophic factors

-loss of dendrites and spines may be from a loss of neurotropic factors following stress: Brain derived neurotropic factor(BDNF) -BDNF is needed for spine growth -neurotropic factors: proteins that the neurons use to grow make new synapses -classic monoaminergic antidepressants and nove antidepressants like ketamine increase BDNF over time through triggering transcription/translation

Depression

-loss of interest in almost everything and inability to experience pleasure (anhedonia). Most patients feel hoplessness, sadness, worthlessness, guilt, desperation -thoughts of suicide are common -last 6-9 months but episodes usually recur throughout life, often increasing in frequency and intensity -Comorbid with other disorders, anxiety disorder, chronic pain, parkinsons, alzheimers

BDNF

-low in the hippocampus and PFC of depressed patients post mortem -BDNF gene polymorphism may be associated with mood disrofers -modifying BDNF gene expression in mice leads to depressive behaviors -early life stress can lead to epigenetic changes that enahnce CRF expression in the amygdale and hypothalamus and decreased glucocorticoid receptors in the hippocampus

Environmental Dependency Syndrome

-mimicking: touch nose, drawing etc, compelled to imitate and continue when asked to stop -stimulus driven: see bed, take clothes off, go to sleep etc -opposite of positive symptoms of schizophrenia as patients with frontal damage do not attend to internal thoughs and voices but are mostly driven by external stimuli

Memantine

-moderate affinity noncompetitive NMDA receptor antagonist -promising clinical relief for those with moderate to severe AD -effects are modest but is one of the medications that is used after other treatments are proven ineffective -only provides short term relief and does not alter the progression of the disease -side effects: dizziness, somnolence, headache, constipation, hypertension

Genes, Development and Schizophrenia

-neurodevelopmental disorder with a strong genetic component -monozygotic: chances are 50% -environment inside and outside the womb plays a role. Chemical triggers in the prenatal environment could trigger genes and epigenetic modifications for those predisposed indivdiuals

First generate antipsychotics (FGA)

-neuroleptics -block D2 receptors -bad movement/motor side effects -long half lives -treat positive and negative symptoms Side effects: extrapyramidal symptoms/movement disorders, sedation, anticholinergic symptoms like dry mouth urinary retention, constipation, disorientation, confusion, endorcrine symptoms, skin, sexual dysfunction, ocular symptoms

Onset and sex difference of schizophrenia

-often begin during the late teenage years and early 20s. gender difference in the age of onset -after age 36 more women than men experience their first episode. before this more men than women

Levadopa

-precursor drug for producing dopamine, increasing dopamine will help some symptoms of PD -dopamine itself does not cross the BBB into the CNS, L-dopa cross BBB -produces dopamine in the plasma, only small portion reaches the brain, nausea is a side effect

Bipolar 2 disorder

-presence of MDD episode -hypomanic episode(less severe than full mania, more irritability) -persistant disinhibition and mood elevation, with behavior that is noticeable different from the persons typical behavior when in a non depressed state. May involve irritability

Mania

-primary symptom of mania is elation, those with mania may have little need for sleep, have unlimited confidence in themselves, and make impulsive disorders -in bipolar disorder you alternate between bouts of depression and mania -feelings of elevated mood, bursting with energy, racing thoughts and actions, irritability 3 for one week every day: -inflated self esteem, decreased need for sleep and does not feel tired, distracted, increased goal directed activity, excessive involvement in actives with high potential for pain ful consequences

Alzheimers

-progressive neurodegenerative disease -creates plaques and tangles in the brain -kills neurons -causes dementia -affects memory, thinking, processing power/speed, judgement, language, decision making

Hypofrontality and schizophrenia

-reduced activity of the frontal cortex -negative and cognitive sympotms of schizo resemble the deficits seen following surgical disconnection of the frontal lobes

Electroconvulsive therapy

-severe cases of depression -side effects significant, memory loss and confusion -performed while under general anesthesia -works quickly

Hypoglutamate + Dopamine Imbalance hypothesis schizo

-too little glutamate and especially in the prefrontal cortex Phencyclidine (PCP) and ketamine produce some schizophrenialike symptoms due to potent blockade of NMDA-type glutamate receptors. NMDA receptor hypofunction results in downstream effects on striatal dopamine, glutamate, and GABA. This may underlie deterioration seen in patients with schizophrenia. Decreased glutamate transmission may be particularly severe in the prefrontal cortex in Glutamate and dopamine interact: 1) less glutamate in PFC, 2) less activity in PFC, 3) less dopamine released in PFC, but 4) MORE dopamine released in NAc. Drugs that block NMDA glutamate receptors (PCP, ketamine) produce symptoms similar to schizophrenia in healthy people and make symptoms worse in patients with schizophrenia. There is reduced activity of the PFC in schizophrenics

Frontal Lobotomy

-treatment for schizo, manic depression and bipolar disorder, among other mental illnesses -enhance negative symptoms: lack of motivation and movement

Compensation hypothesis

-weeks long delayed improvement in symptoms is due to receptor compensation and slow adaptive processes in the brain -when transmitters levels are chronically low, receptors are gradually generated so that the neurons are better at sensing the little that is left. Chronically low serotonin in depressed patients may result in abnormally high serotonin receptor levels -when transmitter levels are abnormally high, post synaptic receptors are removed to reduce sensitivity to the transmitter or more autoreceptors are added to reduce release

Perinatal brain development and schizophrenia

2nd trimester is critical: complications during this period sich as brain insult during pregancy or delivery caused by oxygen deprivation, parenatal drug use, infection, endocrine disorders, severe malnutriotion, and exposure to viral infection can significantly increase risk

Early pain transmission

A delta and C type neurons converge in the dorsal root ganglion of the spinal cord crosses over to opposite side of spinal cord travels up towards the thalamus somatosensory cortex: sensory discrimination of pain and recognizing pain

Muscarinic Receptor antagonists

Anti-ach agents, were used to treat PD before l-dopa -normal movement requres balance between dopamine and acetylcholine transmission; shift in balance results in motor movement disorders, dopamine reduced in PD, either increase dopamine or reduce Ach -Anti-ach agents can reduce tremors but not rigidity or motor slowing -can also produce cognitive dysfunctions

Behavioral approaches to depression

CBT: can be an effective approach to treat depression and anxiety and can be helped when combines with medication -sleep deprivation: can help in some patients and may work by increasing AMPA receptor activation, can produce mania in some patients

COMT inhibitors

Catechol-o-methyltransferase (COMT), enzyme: COMT in GI tract converts l-dopa to inactive -1998 Tolcapone: blocks COMT enzyme, increases half-life of l-dopa but liver toxicity -2001 Entacapone: inhibits peripheral COMT but not central COMT, and increases risk for dyskinesia increased ON-OFF periods -2004 Stalevo, fixed combi pordict with l-dopa, carbidopa and entacapone

Endogenous opioids and their receptors

Endorphins/endomorphins: mu receptor(MOP) Enkephalin: delta receptor (DOP) Dynorphin: Kappa receptor (KOP) Noiciceptin/orphanin: NOP receptor -metabotropic G-protein -made from large precursor peptides made in cell nucleus that are transported to synapse and snipped to make opioids -inhibit neural activity

What produces withdrawal

LC and PAG: injecting opioid antagonists into those of addicted rats results in instant withdrawal symptoms -opioids chronically reduce LC activity. When you stop taking opioids the supression is removed and LC increases actvity/stress because it is involved in arousal, vigilance, anxiety, panic, flight or flight Kappa activation is also involved in the negative feelings of withdrawal

Selective MAO-B inhibitors

MAO exists in two forms:MAO-A and MAO-B -MAO-A is more dominant in the periphery, MAO-B in the brain -MAO-B has affinity for dopamine neurons in the substantia nigra -nonselective MAO inhibitors can be used as antidepressants -Selegiline selectively and irreversibly inhibits MAO-B, inhibits local breakdown of dopamine

Symptoms of parkinsons

Motor: bradykinesia, muscle rigidity, resting tremor, postural balance impairment Nonmotor: sleep problems, olfactory, bowel, mood disorders, cognitive deficits

Where are the opioid receptors

Nucleus accumbens VTA PAG

Pros and cons to opioids

Pros: best pain killers Cons: take too much and die, very addictive

Late pain transmission

Same start as early pain: also makes a stop at the PAG by sending pain information to brain stem regions for pain related behaviors, also descending control (reduction) of pain, lots of opioid producing neurons and opioid receptors, gets inputs from the higher order centers like the frontal cortex, amygdala Thalamus to limbic regions like anterior cingulate cortex and nucleus accumbens

DNA methylation vs acetlyation

Silence gene expression vs activate gene expression

Presynaptic opioid autoreceptors

activates Gi proteins, reduces cAMP, reduces presynaptic Ca2+, reduces excitability less of the colocalized transmitter is released

Post synaptic inhibition

activating G protein receptor eventually opens K+ channels: hyperpolarizes(makes negative) post synaptic synapse or neuron

Chlorpromazine(thorazine)

antipsychotic drug -D2 receptor antagonist -first FGA -high response rate >60 D2R blockade

Parkinsons

degeneration of dopamine producing neurons in the substantia nigra region of the brain

Neurotrophic hypothesis

depression is caused by low levels of BDNF

PAG

descending modulation of pain: origin of most descending fibers many opioid producing neurons in PAG electrical stimulation of the PAG results in strong analgesia PAG projects to raphe (serotonin) and LC which can also reduce pain

tolerance

diminishing effects of a drug with repeated use

Early use FGA vs long term use

dystonia is the principal extrapyrimidal symptom -long: tardive dyskinesia, horrible larger involuntary hyperkinetic, choreiform movements,

Exogenous opioids

exogenous drugs that bind with opioid receptors in the CNS and PNS ex: morphine, fentanyl, Percocet

Dopamins and learning

fast release of dopamine by way of inhibiting inhibitory neurons is thought to trigger learning in the brain for the association between the drug of abuse and drug associated cue

Galen

father of modern medicine, prescribed opium for anti-diarrhea, pain, cough, promote sleep

tricyclic antidepressants

first generation -block the presynaptic reuptake transporter for NE and 5-HT -block post-synaptic receptors for histamine and acetlycholine

Schizophrenia

hear voices, hold unrealistic ideas and beliefs, communicating in a way that is difficult to understand.

Cognitive schizo symptoms

illogical thinking, working memory deficits

First(early pain) vs second(late pain)

immediate, sensory component. signals carried by myelinated alpha delta neurons, which conduct action potentials rapidly vs emotion component, signal carried by thin and unmyelinated c fibers; transmission is slower

Mu opioid agonists

increase dopaminergiv neuron firing -inhibit the inhibitory neurons that inhibit dopamine neurons more dopamine releases in the nucleus accumbens

Mechanism of L-Dopa

inhibiting doap decarboxylase in the body and not in the brain, reduces breakdown of L-dopa before it reaches the brain, L-dopa remains active but only breaks down in the brain -L-dopa needs this unique combination with other drugs for effective action

Environmental factors and depression

intense environmental stress and anxiety often precede episodes of depression -increased stress hormone levels are frequently found in depressed patients with the glucocorticoid cortisol being the most consistently identified -genetics would be one factor why many people seem resilient and capable of coping despite extraordinary stresses while others seem to succumb to relatively minor problems

Heroin

invented by bayer Morphine plus 2 acetyl groups allows it to more easily pass the BBB -converts to morphine in the brain

Negative schizo symptoms

lack of something like emotion, motivation or activity

Emotional component of pain

limbic regions such as the anterior cingulate cortex, prefrontal cortex and nucleus accumbens are involved -regions can exert top down mind over matter control over pain

Monaminergic theroy of depression

logical prediction of this hypothesis is that if you increase serotonin levels you will reduce depression

glucocorticoid hypothesis

long lasting stress causes damage to the HPA axis due to chronically elevated cortisol which ultimately damages the hippocampus

Bipolar 1 disorder

manic episode dont need to depressive episode but it goes with it often

Bipolar disorder

mood swings from depression to mania over time

Laudanum

opium laced wine 1680s to victorian age principle ingredient in opium active ingredient is morphine

Agitation and aggression

pacing, wandering, restlessness, inability to sit long enough to eat -physical resistance and non-compliance with care, psychosis: hallucinations or delusions, depressive symptoms: apathy, lack of interest, inappropriate sexual behavior, sleep disturbances

Aripiprazole (Abilify)

partial agonist at D2 and 5-HT1A receptors and antagonist at 5-HT2 receptors; confers anxiolytic actions

Axo-axonic inhibition

pre-synaptic opioid receptors activate G proteins that close voltage gated Ca2+ channels reducing release

Comorbidity

predicts severe depressive symptoms that are more difficult to treat

Receptor desensitization

progressive failure of the receptors to respond to the drug long term opioid binding

Depressive disorders

recurring episodes of dysphoria and negative thinking -major depressive disorder, seasonal affective disorder, premenstrual dysphoric disorder, persistent depressive disorder

What do opioids do

reduce pain depress respiration suppress cough sedation constrict pupils constipation

Depression vs sadness

sadness is a normal emotion and depression is a combination of factors relating to duration of negative symptoms -depression is beng hopeless about everything

SNRIs and SSRIs

second generation, block serotonin and NE reuptake so more in the synapse -not that selective to 5-HT but also block NE reuptake just like tricylcics -do not work better at treating depression than first gen tricylics/MAOIs but have a fewer side effects -Common: prozac, paxil, zoloft -5HT 1A type receptors is associated with antidepressants and anxiolytic effects -you overdose on SSRIs hallucinations can happen and this may be due to 5-HT2A

Nociception

sensation of pain nociceptors in our skin (PNS) sense pain: free nerve endings(bare dendrites) in the skin that depolarize after painful stimuli, heat, tear, stretch, cold receptors in these dendrites

Acute vs chronic pain

short acting pain, biologically useful vs lasting more than 3 months and nonmalignant

Positive schizo symptoms

something active happening like a hallucination, delusions, or ourbursts of illogical ranting

Endogenous opioids

the brains own chemicals(peptides) that bind with opioid receptors in the CNS and PNS ex: beta-endorphin and enkephalin

Cognitive behavioral theory

therapists work with you to: identify and challenge your own unhelpful cognitive and emotional distortions -develop new behaviors and coping strategies that targe these distortions and bad habits -teaches you to identify your own poisonous thought patterns and then act accordingly -CBT is different from traditional psychotherapy which seeks to identify the unconscious drives and meanings behind the behavior instead CBT focuses more on the here and now

Dopamine hypthesis schizo

too much dopamine in the wrong places -Amphetamine and cocaine creates similar symptoms in non-schizophrenic humans and animals. These drugs increase dopamine concentrations all over the brain. Amphetamine and cocaine makes symptoms worse in schizophrenic patients. Blocking dopamine receptors reduces amphetamine- induced psychosis (e.g., with anti-psychotic drugs) The effective clinical dose of an antipsychotic is best predicted by that drug's affinity for the D2 receptor. PET studies: More D2 receptors in schizophrenic The dopamine hypothesis continued PET studies show more D2 receptors in drug-free schizophrenia patients - especially those with positive symptoms Maybe the increase in D2R is the brain's attempt to reduce dopamine levels? Remember that D2Rs are autoreceptors and autoreceptors are typically involved in turning down the release of dopamine. PET = positron emission tomography. It can measure the activation of a brain region or the concentration of receptors in a brain region

Dementia

umbrella term for impairments in memory, reasoning and other cognitive functions -decline affects daily life -caused by damage to neurons -not normal aging -gradually worsens over time

cross tolerance

when one opioid drug makes you less responsive to another opioid drug