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PSYD35H3 (3)
Midterm

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Department
Psychology
Course
PSYD35H3
Professor
Nussbaum D
Semester
Winter

Description
Lecture 5- ANXIOLYTICS (GABA & BENZOS) • Neuroanatomy: ETKIN 1) core limbic group (amygdala, insula, hypothalamus) register stimuli and coordinate physio/beh response to them Dorsal medial prefrontal (and anterior cingulate)—involved in extensive evaluation of emotions (and make things conscious) rostal and subgenual anterior cingulate and VMPFC—context specific regulation of emotion • LPFC may aid in regulating anxiety and emotions Benzos • Historically benzos were named by their structure, now named by what receptor are active • GABA agonists • Nucleus: 2 rings sharing carbon attached to third ring by carbon bond • Ring A (portion composed of benze) fused to Ring B (7-diazepam) and attached to Ring C (aryl ring) • Action: GABA activation • Benzo receptors located on alpha sub unit of GABA---almost exclusively post synaptically • Action: opening of more Cl channels on post synaptic cell, hyperpolarization—by reconfiguring receptor so GABA molecules attach/activate receptor more effectively • Benzo drugs are defined by the combination of side-groups at radical 4 and 5 • GABA: COOH-CH2-CH2-CH2-anime end • GABA synthesis: Glutamate+enzymeGlutamic Acid Decarboxylase (GAD)GABA • Termination I: presynaptically by enzyme GABA tranamine (GABA T) • Termination 2: removed from cleft by GABA transporter into presynaptic---destructed by GABA T • Binding sites: GABA a: anti-anxiety effects exclusively; GABA b: not really understood, related to cardio, impulsivity • GABA inhibits neurons in amygdala that respond to fear—relieving fear • When GABA receptor unoccupied: Cl channel closed (easily excitable); when occupied: Cl channel is open= relatively unexcited (inflow of hyperpolarizing Cl) 1 • GABA neurons in visual cortex and insul innervate amygdala—so when activated, inhibits activity • People with panic disorder have less benzo binding in insula and PFC • Benzos: combat anxiety, sedative, anticonvulsant, amnestic, relaxant • AO: amygdala, OFC, insula; anticonvulsant: cerebellum, hippocampus; confusion: cortex, hippo; relaxant: spinal, cerebellum, stem • Completely aborbed orally, and peak plasma in 60min (lorazapam/oxazepam absorbed slower) • Metabolism: diazepamactive metabolite noriazepam inactive metabolite glucuronide- cojucated)poo • Lorzepamdirectly transformed to inactive (glucoronide-conjucted)poo • Long acting benzos (diazepam)long half lives, metabolites have long half lives • Complete benzo agonists: anti-AO, confusion, amnesia, muscle relaxant • Rebound effects: increased anxiety; withdrawal, abuse because of negative reinforcement, adie effects: ataxia, sedation, memory+cog impairment • • Non-benzo (zolpidem) but work at GABAa type 1 receptor: quickly sleep—like short acting • Zaleplon`: non benzo, rapid-onset, acts at GABAa1, no rebound (zopiclone is similar but longer acting) • Benzo that are agonist at 5H receptors: ligand-gated channelsactivation cause inhibition • Buspirone (SSRI) doesn’t cause benzo or alchy side effects, no dependence, little abuse potential, not sedative • Benzos great for seizures, GABAa inhibit GLU • Phenobarbital: first effective anti-epileptic, neuropsych deficits, favourite Hollywood suicide drug • Phenytoin/Dilantin less toxic than ^ 2 • Carbamzepine: used before for bipolar, less sedating than ^, immunity side effects though • Valproic acid: enhances post-synaptic GABA effectiveness, good for explosive and aggressive disorders, seizures • Lamotrigine: anticonvulsant, also used for bipolar; treats partial seizures, mood stabilizer, few side effects (Ma channel blocker) Main points of chapter: • Benzos major advantage over barbs: never fatal unless combined with alcohol • Theses drugs are GABA receptor agonists • Benzos: bind to site near GABA receptor, increasing affinity of GABA for receptor—act at limbic center---amygdala OFC, insula • Hypofunctional GABAa receptor may sensitize amygdala to anxiogenic responses • These drugs can cause blackouts, antergrade amnesia, dementia (beh/cog/iq deficits) • Barbs: rarely used now, suicide and accidental OD death, hypnotic action in short acting is terminated by redistribution, other barbs terminated by rate of metabolisms • Bars are well absorbed orally, very lipid soluble • Barbs low degree of selectivity—NOT ANALGESTIC • Barbs depress memory functioning—cognitive inhibitors, motor, judgment, coordination, respiration all affected • Similar effects as alchy • Barbs use declined: lethal in OD, narrow TI, high potential for tolerance, interact dangerously with many other drugs • DOWSINESS, judgment, intellectual performance re all adversely affected • Tolerence caused by: dug-metabolized enzymes in lover, adaption of neurons in brain • Withdrawl: hallu, restlessness, disorientation, convulsions • Nonbarbs: ethchlorvynol, methyprylon—dfiferent nucleus but act at same sites---no advantages, obsolete • Meprobamate: sedatation.anxiolysis, mild euphoria, relief of anxiety 3 • Carsoprodol.: precursor and rapidly metabolized to meprobamate (active form) • Methaqalone: aphrodisiac, date rape • GHB: used outside US as anesthetic---similar to alchy amnestic, excitement, drunk, excitement affects, rapid onset- 30 min, od= stupor, delirium, coma, death (used for narcolepsy)---abused as euphoria and aphrodisiac • Benzos: widely used today—well absorbed taken orally, within an hour • Long acting: long half life of active metabolite (short acting have shorter half-life for metabolite) • Some benzos are metabolised into intermediate active products than metabolized, others are directly metabolized • All benzos: cognitive dysfunction and dementia in elderly, more falls, confusion, and stay in system weeks longer • All benzos are pure GABA agonists: easy to use, low toxicity, effective in producing tranquil state • Benzos can increase depressive symptoms though, and cog impairments • Benzos are good for short term treatment of anxiety, and as muscle relaxants • Produce anterograde amnesia; panic attacks treated with alprazolam • Benzo can substitute alchy, to treat withdrawal, also used as anticonvulsant • Toxicity: insomnia, above ^ slurred speech—REM rebound (insomnia and anxiety), motor impairments, learning, psychomotor, academic • Tolerance: insomnia, agitation, unpleasant dreams, hallucinations, psychosis, seizures • Floopy-infant syndrome, abnormalities for fetus • Flumazenil: GABAa antagonist—no intrinsic activity—blocks access to receptor for other drugs, reversing antianxiety, rapidly, is ANTIDOTE TO BENZO OD • Benzo receptor agonist (BZRA)—lower doses benzos have anti-anxiety effect; high doses: hypnotic(sedative) • Bzra: Triazolam: shortest half life, 2-4 hours, least sedation • Nonbenzo-BZRAS: Zoplidem: treatment for insomnia, hypnotic effect, rapidly absorbed, promotes sedation, muscle relaxant, drowsiness 4 • Zaleplon(BZRA): similar action to ^ but is very short and no real side effects (don’t predict if will have insomnia, can just take it) • Full BZRAs are effective but use is limited by rebound anxiety, so partial agonists are being used • Buapirone is 5HT1a agonist with Antianxiety features: no hypnotic/sedation, o confusion, impairment, doesn’t interact with alchy, no cross tolerance, gradual onset---it is a SSRI used to treat lots of anxiety disorders • Buspirone best for patients with anxiety not looking for immediate relief ----------- LECTURE 6: COCAIN & AMPHETAMINES • Cocaine: used to be local anesthetic • Stims: Fight/flight response, increase bp, dilate pupils, increase 02 and glucose use, • Stims: Elevates mood, euphoria, relieves boredom, reduces fatigue, decrease appetite, improve task performance • Use: not inappropriate; abuse: immediate/long term harm; addiction: most important aspect of life • Mechanism: all stim use synaptic actions of dopamine; beh reinforcing, medical use, significant side effects • Low dose: alert, adrenaline surge, elevated mood, euphoria, vigilance, energy • Effects: anxiety, insomnia, restlessness, anxiety, psychotic behaviour • Increase DA transmission in: VTA->NA->Frontal Cortex • Transmission facilitated: 1) transported into vesicles in presynaptic cytoplasm 2) enhanced transportation of vesicles to pre-synaptic membrane 3) kept in cleft to enhance • Cocaine mechanism: binds to DA reuptake transporters on presynaptic membrane of DA neurons in reward center (VA,NA,Caudate) binding inhibits prevents DA removal from cleft= excessive= euphoria/high • Short action, metabolized to benzoylecoginine, metabolized abnormally ethanol present • Half-life 2.5 hours 5 • Major metabolite: benzoylecognine (BE) and others (EME and econin); metabolized by hydrolytic ester • Cocaine +alchy: froms cocoaethylthen in liver (more cardio toxicity and more euphoric than cocaine—dopamine agonist) • Tolerance: increased hr, bp, ; no tolerance: insomnia, decreases REM • Overdose: muscle weakness, respiratory depression, Cardiac toxicity (Caine reaction: initial high headache, nausea, vomiting, convulsions, LOC, death—takes 2-30min • Sex effects: decreased drive over time (initially excites) • Sensitization: continual high doses causes steroytypy • Cocaine toxicity: anxiety, sleep deprivation, restlessness, paranoia, fearfulness, hyper vigilance, aggressive • Psychostims: cocaine, ampth m-amph, khat, cathinone, ephedrine • Cocaine testing: urine up to 12 hours, BE metabolite up to 48 h • Cocaine: local anesthetic, vasoconstrictor, stim; shot half-life (mins), more recreational • Meth: long half-life, irreversible brain changes, used continuously over 20x month, .5- 1g/daily~ • Amphetamines: sensitization makes psychotic behavioural indistinguishable from schizophrenia (hallu,delusions, formication (bugs on skin)-->therapeutic use (narcolepsy, ADD, obesity) 6 Amph Cocaine • Low dose of Amph increases DA in cleft by: 1) bind to pre synaptic membrane and trigger release of DA from terminal 2) interact with DA vesicles to release DA in terminal 3) bind to DA reuptake transporter, prevents reuptake and reversing so DA is released from terminal • High dose of Amph: modify action of NE and DA and Increases DA in cleft in 4 ways: all of the above and *bind to MAO in DA neurons to prevent destruction of DA—more DA in terminal • Amph and cocaine has similar kinetics. Amph has longer duration (hours); cocaine (30- 90min); cocaine less potent orally (60% as potent when IV’d); cocaine is local anesthetic, amph is not • Treating Amph may require AD, anti-psychotics, mood stabilizers • Meth: a bunch of bad side effects we all know • In WWII: Amphs used for fatigue; after war: used for weight and depression; fatal dose: . 3-1.7g • Epidemic slowed becau
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