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TULANE / NSCI / NSC 4530 / psychopharmacology study guide

psychopharmacology study guide

psychopharmacology study guide

Description

School: Tulane University
Department: NSCI
Course: Psychopharmacology
Professor: Donhanich
Term: Fall 2016
Tags: neuroscience, psychopharmacology, and neuropsychopharmacology
Cost: 50
Name: Exam 2 Psychopharmacology Study Guide
Description: Comprehensive study guide including notes on the lectures, powerpoint and associated readings.
Uploaded: 10/27/2016
32 Pages 10 Views 13 Unlocks
Reviews


Thursday, October 27, 2016


what is the meaning of catecholamine synthesis?



Exam 2

Psychostimulants  

• main psychostimulants: cocaine and amphetamine

• mainly affect catecholamines  

• catecholamines

• catechol nucleus

• benzene ring + 2 adjacent OH groups

• amine group (NH2)

• basic

• catecholamine synthesis:

• process: tyrosine, DOPA, dopamine, norepinephrine, epinephrine

• all are metabolites of each other  

• tyrosine is an amino acid (NOT catecholamine bc no adjacent hydroxyl groups) • tyrosine —> DOPA  

• via tyrosine hydroxylase (TH)

• TH adds adjacent OH group onto the benzene ring

• DOPA is a catecholamine

• TH is rate limiting enzyme

• DOPA —> dopamine  

• via aromatic amino acid decarboxylase (AADC)

• gets rid of COOH from alpha carbon

• dopamine —> norepinephrine  

• via dopamine beta-hydroxylase (DBH)


what is epinephrine degradation?



• this adds an OH to the center carbon

• norepinephrine —> epinephrine  

• via phenyethanolamine N-methyltransferase

• adds methyl group to nitrogen (makes NH-CH3)

• synthesis can be increased by L-DOPA (precursor)

• high catecholamine levels inhibit TH - negative feedback effect  

• storage:

• catecholamines stored in synaptic vesicles inside presynaptic membrane • vesicularization - vesicular monoamine transporter (VMAT2)

• protein channel takes up dopamine after synthesis and packs them into vesicles • H+ ions pumped into vesicle to maintain low pH (this is so they do not diffuse out of the  vesicular membrane - at a high pH, they would become unionized and lipid soluble) • stops enzymes from breaking down neurotransmitter

• controls rate of release, controls quantum nature of release

• reserpine


what is isoproterenol?



• reserpine blocks vesicularization of monoamines

• free monoamines degraded by MAO (monoamine oxidase)

• ultimately depletes brain of monoamines

• induces sedation, reduces blood pressure, implicated in mental disorder theories • has been shown to reduce schizophrenia symptoms, increase depression’s symptoms • release If you want to learn more check out biology chapter 5 notes

• controlled by calcium influx

• regulates enzymes that control moving towards membrane, docking, fusing, etc 1

Thursday, October 27, 2016

• calcium enters via voltage-gated ion channels  

• cluster of proteins in synaptic vesicle

• budding

• filing with neurotransmitter

• packing of nt prevents it from being degraded by enzymes

• docking and priming

• exocytosis - fusion with membrane caused by calcium  

• release inhibited by auto receptors (these open K+ channels) We also discuss several other topics like What are the three types of bacteria?

• removal from synapse via reuptake (via transporters) OR degradation

• catecholamine transporters act in reuptake: in membrane of presynaptic membrane • DAT - reuptake of dopamine

• NET - reuptake of norepinephrine

• dopamine degradation (2 methods) into homovanillic acid Don't forget about the age old question of jacqueline evans fiu

• mainly broken down via catechol-O-methyltransferase (COMT) or monoamine oxidase  (MAO)

• 1. dopamine —> 3-methoxytyramine (3-MT)  

• via COMT

• 3-MT —> homovanillic acid (HVA)

• via: MAO and aldehyde dehydrogenase

• 2. dopamine —> 3, 4 dihydroxyphenyl-acetic acid (DOPAC)

• via: MAO and aldehyde dehydrogenase

• DOPAC —> HVA cia COMT

• **measuring levels of HVA can tell you how much dopamine was there in general • norepinephrine degradation (2 methods)

• 1. norepinephrine —> normetanephrine  

• via COMT

• normetanephrine —> vanillylmandelic acid (VMA)

• via MAO

• 2. norepinephrine —> dihyroxymandelic acid  

• via MAO

• dihyroxymandelic acid —> vanillylmandelic acid (VMA)

• via COMT

• epinephrine degradation (2 methods)

• 1. epinephrine —> dihyroxymandelic acid

• via MAO

• dihyroxymandelic acid —> vanillylmandelic acid (VMA)

• via COMT

• 2. epinephrine —> metanephrine

• via COMT

• metanephrine —> vanillylmandelic acid (VMA)

• via MAO

• metabotropic receptors:

• D1

• D2

• D3

• D4

• norepinephrine: can work through different types of receptors that link to separate 2nd  messenger systems (gives flexibility)

• a1

2

Thursday, October 27, 2016

• activates PLC

• contest pip3 to DAG and ip3 We also discuss several other topics like dwight a. roblyer
We also discuss several other topics like balance is achieved when all elements in a work of art are equidistant from a central point and repeat in a symmetrical way from side to side and top to bottom

• IP3 causes calcium to stimulate smooth muscle contraction

• —> phosphoinositide stimulated

• a2

• inhibition  

• Gi protein

• decreases cAMP activation

• B1

• activation increases cyclic AMP

• Gs protein

• contracts heart muscle

• B2

• B3

• release regulated by autoreceptors

• located in presynaptic membrane

• NOT the same as reuptake!!!

• bind neurotransmitters onto presynaptic membrane

• inhibit transmitter release (like “brakes” for the system) - inhibits calcium entry into the cell • D2 - for dopamine

• �2 - for norepinephrine

• most cell bodies of catecholaminergic neurons found in mesencephalon (project from  mesencephalon to higher areas) We also discuss several other topics like What are the types of sampling design?

• nigrostriatal pathway (dopamine)

• substantia nigra (A9) to striatum (caudate-putamen)

• mediates movement, coordination

• mesolimbic pathway (dopamine)

• VTA (A10) to nucleus accumbens

• reward, reinforcement (mediation of drug dependency, addiction)

• mesocortical pathway (dopamine)

• VTA (A10) to cortex

• coherent thinking, concentration, etc.

• tuberoinfundiblar (A12) pathway (dopamine)

• more of a hormonal pathway

• arcuate nucleus —> median eminence

• median eminence —> anterior pituitary  

• dopamine dumped into portal vessels

• DA inhibits prolactin release

• milk synthesis

• noradrenergic pathway (norepinephrine)

• locus coeruleus (A6) to higher brain regions

• arousal, attention, focus, wakefulness

• neurotransmitters do not interact directly with drugs

• typical drug targets

• receptors

• transporters

• autoreceptors

• enzymes

• reuptake blockers: increase transmitter in synapse

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Thursday, October 27, 2016

• autoreceptor agonists: decrease transmitter release

• enzyme inhibitors: increase transmitter levels

• amphetamine/meth can cause release of catecholamines without nerve cell firing • cocaine: erythroxylon coca

• plant derivatives: bases containing nitrogen (nitrogenous bases)

• Peru, Bolivia, Columbia

• preparations:  

• leaves

• cocaine HCL (salt)

• cocaine base (free base)

• pressed to purify, get rid of the liquid

• leaves softened, toxic things added (gasoline)

• created LOTS of waste

• processing:

• coca leaves

• chewed to absorb buccal (free-base form)

• some chew something with it to make mouth more basic to unionize more cocaine • doesn't cause dependency

• coca paste made from leaves (still in basic form)

• toxic chemicals added to be able to snort and make cocaine HCl

• cocaine HCl

• stable salt, most purified

• best for export due to stability (won’t break down for a while)

• CANNOT be inhaled

• water-soluble

• degraded before vaporizing (vaporization point higher than degradation point) • this causes little effect because much is destroyed before absorption

• used to only be used in this state

• cocaine base:

• free base

• water insoluble  

• process:

• mix cocaine HCl with ammonia

• extract precipitate with ether (ether very flammable and explosive)

• evaporate ether - vaporizes

• now free base that can be inhaled for absorption (put in pipe)

• crack cocaine

• mix cocaine HCl with baking soda (sodium bicarbonate)

• heat

• filter precipitate

• wash precipitate and dry - now can be smoked  

• can be made without dangerous ether

• administration

• leaves - buccal

• HCL - intranasal, intravenous

• base (free base or crack) - inhalation

• absorption and distribution

• weak base

• increasing GI absorption with increasing pH

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• rapid absorption intranasally

• very rapid absorption via inhalation (almost like injection)

• onset and duration of action

• intranasal: onset in minutes, duration of 60 minutes

• inhalation: onset in seconds, duration of 15 minutes

• distribution:

• crosses blood brain barrier

• plasma cocaine concentrations:

• IV and smoking are very rapid, shorter duration

• cocaine biotransformation:

• metabolism:

• via liver

• first order

• major metabolites (ecgonines)

• benzoylegonine

• cocaethylene

• half-life

• after around 4 hours, drug eliminated from plasma

• metabolite persist up to 3-5 days after last administration, much longer in heavy users • detection depends on sensitivity of procedure

• mechanisms:

• cocaine action at synapse:

• blocks reuptake of dopamine (blocks DAT) - due to large size

• increases dopamine concentration in synapse, which activates reward system • could also block uptake of serotonin (SERT) and norepinephrine (NET) • blocks sodium channels locally

• need both dopamine and serotonin for cocaine to have effect?

• acute effects: cocaine and amphetamines have very similar effects

• cognitive and behavioral effects:

• arousal, alertness, wakefulness

• involved with locus coeruleus to higher brain regions system

• noradrenergic

• more energy

• decreased distractibility, increased concentration

• VTA to cortex pathway (thinking)

• dopaminergic

• confidence, well-being, euphoria (intense - most powerful)

• reward pathway - VTA to nucleus accumbens

• dopaminergic

• increased general activity, improved physical performance

• substantia nigra to striatum - movement system

• dopaminergic

• body weight effects

• increased general activity (nigrostriatal)

• suppressed appetite (hypothalamic mediation)

• decreased digestion (mediated by sympathetic system)

• digesting less effectively

• reduced body weight

• some use amphetamines to control body weight  

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Thursday, October 27, 2016

• peripheral side effects (sympathomimetic effects)

• increased heart rate

• increased blood pressure

• increased respiration rate

• dilation of airways

• dilation of pupils

• inhibited digestion

• decreased salivation

• urinary retention

• increased cellular metabolism

• increased body temperature

• toxic effects:

• headache

• dizziness

• confusion  

• agitation

• fatigue

• insomnia

• nasal bleeding

• seizures - uncontrolled firing in the brain

• cardiac arrest

• associated with cocaine use

• stimulant psychosis - very similar to schizophrenia

• paranoia

• delusions

• stereotypy

• hallucinations (usually visual and tactile)

• effects of cocaine on cardiovascular system

• increases demand on the heart (sympathetic)

• increases heart rate and force

• increases blood pressure

• reduces heart function

• constricts coronary artery —> this reduces oxygen reaching heart

• exerts direct toxic action on heart

• potential consequences:

• cardiac arrhythmia  

• heart stoppage or cerebral stroke (hemorrhage)

• sympathetic control of cardiac muscle

• a2 autoreceptor on sympathetic nerve

• increased NE DECREASES heart rate

• B1 and B2 receptors in the heart

• increased NE, causes heart rate and force to increase

• over activation of B1 receptors by NE contributes to cardiac arrhythmia • increased force of myocardial contraction

• increased rate of contraction

• excess stimulation leads to arrhythmias

• people with arrhythmia issues often take beta blockers (these block Beta receptors) • cocaine’s therapeutic uses

• local anesthetic: ONLY approved medical usage for cocaine

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Thursday, October 27, 2016

• due to blocking of sodium channels

• used in surgeries:

• eye

• ear/nose/throat

• urinary tract

• reduces blood flow to site of administration (restricts blood vessels)  

• substitutes:  

• procaine

• lidocaine

• novacaine

• “Uber Coca”

• Freud used himself to record cocaine’s psychological effects

• didn’t pay enough attention to its anesthetic uses

• better than ether and chloroform because they cause vomiting

• Koller: dropped cocaine in eye of a dog - felt nothing when needle later poked it • likely that Freud neglected this because the other effects are so strong

Amphetamines

• **keeping nt inside vesicles is similar to ion trapping - pH used)

• drug names:

• 1. chemical : (S)-1-phenylpropan-2-amine

• 2. generic: dextroamphetamine

• 3. trade: dexedrine

• amphetamines: very similar in structure to norepinephrine

• formulations of amphetamine:

• dextrolevoamphetamine (Benzedrine)

• racemic (both isomers)

• least potent

• dextroamphetamine (Dexedrine)

• active isomer (only one of the two)

• dextromethamphetamine (Desoxyn)

• most potent form in CNS

• likely because it enters the brain more easily

• added methyl group to amphetamine

• isoproterenol  

• stimulates beta-adrenergic receptors, which are only on some sympathetic tarter organs  (including bronchial muscle)

• doesn’t cross BBB, so doesn’t have much CNS stimulation (makes it good for medication) • does have adverse heart effects bc beta adrenergic receptors are there too • administrations:

• all forms: oral

• methamphetamine powder: intranasal and IV

• burned methamphetamine crystals: inhalation

• absorption:

• weak base:

• increasing pH increases GI absorption rate (orally)

• very rapid absorption via inhalation

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Thursday, October 27, 2016

• onset/duration of action  

• oral: onset in 30 min, variable duration

• inhalation: onset in seconds, duration of 15 min

• distribution: crosses BBB

• metabolism

• via liver

• first order

• elimination

• increased excretion at lower renal pH (very susceptible to the effects here) • due to basicity  

• half-life

• 6-36 hours depending on renal pH (wide range)

• metabolites persist up to 3-5 days after last administration, much longer in heavy users • mechanisms

• subvert reuptake mechanisms for NE and E

• attachment causes transporter to release NE

• amphetamine recognized as NE, so actually enters the cell (via reuptake) • leakage of DA/NE because such a large concentration already inside cell • increased pH inside vesicle due to amphetamine

• this causes unionization of NE/DA and they start leaking through membrane • inhibits MAO to reduce DA/NE breakdown (MAO goes after amphetamine, so there is  less to break down dopamine and norepinephrine)

• reverse transport of DA/NE into synapse (nt leave through same transporter) • —> increases catecholamine release!

• mimic activation of the sympathetic nervous system - increases function of norepinephrine/ epinephrine

• acute effects: VERY similar to cocaine

• cognitive and behavioral

• arousal, alertness, wakefulness, energy

• increased concentration, decrease in distraction

• confidence, euphoria, sense of well-being

• euphoria caused by dopamine in VTA

• increased activity, improved physical performance

• body weight

• increases general activity, suppresses appetite, decreases digestion

• reduces weight

• peripheral side-effects (sympathomimetic)

• increased heart rate, blood pressure, respiration

• dilation or airways and pupils

• inhibited digestion

• decreased salivation

• urinary retention

• increased metabolism and body temp

• toxic effects:

• headache, dizziness, confusion, agitation, fatigue, insomnia

• seizures, cardiac arrest

• dental disease - “meth mouth”

• dry mouth (sympathetic activation - thickened saliva)

• clenching (Bruxism)

8

Thursday, October 27, 2016

• poor hygiene

• stimulant psychosis - possibly due to dopamine dysfunction

• paranoia

• delusions

• hallucinations

• stereotypy - highly repetitive motor patterns

• neurotoxicity: not associated with cocaine, just amphetamines

• measures of dopamine transporter via PET scan  

• fewer axons in dopaminergic neurons due to amphetamine (looks similar to those with  Parkinson’s)

• —> loss of striatal DA in stimulant abusers  

• therapeutic uses:

• legal uses (2):

• narcolepsy

• ADHD - helps them increase concentration (not necessarily calm down) • most common condition treated by amphetamines

• paradoxical effect: amphetamines used to treat both narcolepsy and ADHD • off-label therapeutic uses (physicians prescribing drugs that are approved, but not for what  it has been prescribed)

• obesity

• very ineffective, due to quick tolerance build-up

• depression - very low doses, not a typical treatment

• ADHD subtypes:

• predominantly inattentive

• hyperactive/impulsive

• combined

• is ADHD a dysfunction of the PFC? - mechanisms unknown  

• working memory

• executive function (right PFC)

• attention

• planning

• impulse control

• mental flexibility

• monitoring actions

• PFC lesions (right) lead to issues with above functions

• distractibility

• disorganization

• impulsivity

• perseveration - repeating words/thoughts/actions

• forgetfulness

• PFC confers inhibition on other brain regions  

• mostly motor structures - no inhibition via PFC leads to hyperactivity

• basal ganglia: striatum (caudate) and subthalamic nucleus

• cerebellum (via pons)

• motor and premotor cortices

• dopamine modulates neuronal excitability in frontal cortex and limbic

• in ADHD, reduction of DA in the PFC  

• hypofrontality: low cortical function - under active

• dopaminergic neurons projecting to PFC cause its inhibition activity

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• DA from VTA to cortex (in ADHD, these neurons are not providing a strong enough  signal for the PFC to exert a large enough inhibition for movement)

• noradrenergic system: locus coeruleus to PFC

• also insufficient in ADHD - causes lack of inhibition  

• microdialysis: measurement of transmitter release in specific brain area • animal is awake and alive/behaving

• gives real-time measurement of which neurotransmitter being released • methylphenidate (MPH - ritalin) injection

• immediate large increase of NE and DA in PFC

• stimulants activate alpha 2A and D1 receptors in PFC

• optimal levels of activation between NE and DA

• **dextro isomer is more potent, levo is less potent**

• ADHD treatment formulations (daily doses)

• dexedrine - dextroamphetamine (1-3)

• dextro - right handed isomer (more potent)

• adderall - amphetamine salts (1-3)

• mixture of 4 isomers (2 dextro and 2 levo)

• 4 types of amphetamine salts

• dextro more potent - more in plasma than levo after same time period

• ritalin - methylphenidate (2)

• concerta - methylphenidate ER (1) - extended release

• daytrana - methylphenidate ER (1) - extended release

• strattera - atomoxetine (1-2)

• non stimulant - NOT an amphetamine

• noradrenergic reuptake blocker

• less effective than psychostimulants

• lower risk of abuse

• vyvanse - lisdexamfetamine (1)

• prodrug - converted to D-amphetamine once administered  

• longer duration of action

• lower risk of abuse

• therapeutic effects of psychostimulants for ADHD

• improve attention span and focus

• increase ability to follow directions

• decrease distractibility

• decrease impulsivity, stubbornness, aggression

• ADHD psychostimulants side effects

• increased heart rate and blood pressure

• nausea, dizziness, headache

• insomnia

• poor appetite, weight loss

• suppressed growth - not necessarily permanent

• cardiovascular issues

• abuse potential - usually moderate doses and tolerance doesn’t increase too much, so  abuse potential is low

• paradoxical effects: zombie-like affect  

• methylphenidate increases DA release in PFC more effectively than in nucleus accumbens • potential for abuse may be low because the nucleus accumbens in not as activated (PFC  more targeted by stimulants)

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• amphetamine-like compounds

• ephedrine (ma huang) - natural plant  

• stimulant, anti-asthma

• dilates bronchial tubes

• stimulate respiratory centers in medulla

• first general stimulant

• not for severe asthma, but for bronchial congestion

• meth made from these (at home)

• can get pseudoephedrine from pharmacy

• fenfluramine (serotonin releaser) - approved drug for weight control

• affects serotonin release in hypothalamus

• phenylephrine (�1 agonist) - decongestant (widens blood vessels)

• tolerance built up very quickly, and rebound from stopping spray is bad • bath salts

• stimulants  

• cathinone (khat plant extract)

• synthetic cathinones, mephedrone

• intranasal, oral, IV, IM

• strong amphetamine-like effects (banned in most states)

• drug tolerance

• reduced effect after repeated administration

• increased dose restores original effect

• tolerance varies wth different drugs and drug effect within given drug

• people on cocaine/amphetamines typically don’t do drugs every day

• will go on binges, and then withdrawal begins

• psychostimulant tolerance

• rapidly forming

• appetite suppression - this is why they are bad for weight-control

• euphoria

• cardiovascular effects

• lethal effects

• slowly or non forming (2 approved uses because the tolerance is not bad) • effect on narcolepsy

• effect on ADHD

• reverse tolerance (sensitization)

• seizures

• having one seizure on amphetamines means you’re at greater risk for seizure in  the future (sensitized to drug)

• locomotion

• animal that’s been on amphetamines for a while will have a large increase in motor  activity

• physical dependence

• withdrawal syndrome

• opposite of acute effects

• psychological dependence

• positive reinforcement effect of drug

• psychostimulant dependence

• physical (withdrawal symptoms) - not very strong with cocaine and amphetamines • fatigue/exhaustion

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• prolonged sleep

• depression/crash

• intense hunger

• psychological

• extremely powerful

• very high on scales in comparison to other drugs

• reinforcement property accounts for abuse

• intense craving

• anhedonia - nothing makes you happy but the drug

• self-administration by animals (will bar press until death)

• physical dependence model (Wikler)

• initial drug use —> repeated use —> physical dependence —> attempts at abstinence —>  withdrawal symptoms —> relapse —> attempts at abstinence —>….

• Koob: positive reinforcement

• initial drug use —> repeated use —> attempts at abstinence —> compulsive desire to re experience drug-induced euphoria —> relapse —> attempts at abstinence —>…. • mesolimbic pathway (DA)

• VTA —> nucleus accumbens

• cocaine blocks DA reuptake

• prevents dopamine transporter from working, which allows DA to accumulate • amphetamine stimulates DA release

• amphetamines bind to transporter and are carried into the neuron

• promote the leakage of DA from vesicles

• intracellular DA transported outwards

• positive reinforcement

• self-administration

• conditioned place preference

• determine pre-drug compartment preference

• condition non-preferred side to drug

• condition side to vehicle

• test post-conditioning preference without drug

• incentive-sensitization model (Robinson): brain becomes sensitized to effects of drug • this increases DA activity and alters brain structure

• dendritic remodeling in nucleus accumbens

• axons from VTA release dopamine

• increased spines

• dopamine in NA is key factor in drug addiction

• xanthine: purine related to uric acid

• caffeine, theophylline

• caffeine inhibits phosphodiesterase, which metabolizes cAMP

• blocks adenosine (depressant)

Nicotine

• nicotiana tabucum: tobacco leaves

• acts as insecticide - binds to receptors and causes inhibition of transmitters in bugs  • preparations

• cigarettes

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Thursday, October 27, 2016

• enters lungs on tiny tar particles

• cigars

• pipes

• e-cigarettes

• smokeless

• patches

• gums

• plant alkaloid

• 2 connected ring structures with nitrogen

• base with pKa 8.5

• administration

• inhalation (most effective - even quicker than IV)

• nicotine reaches brain in about 7 seconds

• buccal

• nasal

• transdermal

• nicotine in cigarette smoke must be inhaled to be absorbed well because cigarette smoke is  acidic

• lungs have a more acidic pH than the mouth  

• nicotine only will be lipid soluble in more acidic pH

• in more basic, nicotine is more ionized  

• cigar smoke is basic, so it can be absorbed in mouth

• biotransformation

• nicotine with half life of 2 hours

• complex metabolism

• 70-80% oxidized to principle metabolite cotinine (half life of 16 hours) • via cytochrome P450 2A6

• individual variability in rates of nicotine metabolism

• fast metabolizers consume more, less likely to quit

• caucasians faster than Asians/African-Americans

• females faster than males

• mechanisms

• main transmitter is Acetylcholine

• ACh: acetate + choline

• synthesis:

• choline + acetyl CoA —> ACh  

• via ChAT (choline acetyltransferase - ONLY in cholinergic neurons)

• transfers acetyl group from CoA to choline

• found only in neurons that use ACh

• inside presynaptic neuron

• choline comes from fat in our diet

• acetyl CoA comes from metabolism of sugars and fats (

• rate of synthesis controlled by

• availability of precursors

• rate of cell firing

• VAChT: vesicular ACh transporter (loads ACh into vesicles)

• blocked by drug called vesamicol - this deceases vesicular ACh but increases  cytoplasmic ACh (because doesn’t effect synthesis at all, just vesicular uptake) • degradation

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• ACh —> choline + acetate

• via AChE (acetylcholinesterase - not always in cholinergic neurons)

• found inside presynaptic cell to metabolize excess

• also found in postsynaptic to break down after release into synaptic cleft • some at NMJ to stimulate muscle contraction

• these very important because break down ACh immediately after muscle  contraction so that muscle can relax until next command

• drugs that block AChE prevent inactivation of ACh - this increases postsynaptic  effects (ex: physostigmine - crosses BBB)

• once ACh broken down, choline taken back up int cholinergic nerve terminal • HC-3 (hemicholinium-3): blocks choline transporter  

• hard to find highly selective inhibitors of ChAT

• myasthenia gravis: neuromuscular disorder in which patients develop antibodies against their  own muscles' cholinergic receptors

• helped by neostigmine, pyridostigmine (similar to physostigmine except don’t cross BBB) • these drugs are reversible AChE inhibitors  

• some irreversible AChE inhibitors that have been used as nerve gases in chemical warfare  (Sarin, Soman) —> overstimulation of cholinergic synapses

• death due to asphyxiation from diaphragm muscle paralysis  

• preganglionic neurons of both sympathetic and parasympathetic cells are cholinergic • postganglionic neurons of parasympathetic is cholinergic as well

• cholinergic nerve cells in striatum are interneurons

• cholinergic pathways in the brain (2)

• 1. basal forebrain cholinergic system (BFCS)

• involved in Alzheimer’s

• cell bodies:

• medial septum MS

• diagonal band DB

• nucleus basalis nBM

• axon terminals (could be nicotinic OR muscarinic receptors)

• cortex

• hippocampus

• limbic system

• 2. dorsolateral pons - brainstem cholinergic system  

• cell bodies

• lateral dorsal tegmentum LDT

• peripeduncular tegmentum PPT

• axon terminals (could be nicotinic or muscarinic)

• ventral tegmental area (VTA)

• midbrain dopaminergic cell groups

• dopamine release in nucleus accumbens after nicotine injection

• nicotinic receptors

• ionotropic

• 5 protein subunits with central sodium ion channel (calcium can enter as well) • 2 ACh binding sites, both need to be occupied to open receptor channel • mediates fast excitatory responses in CNS and PNS

• areas:

• skeletal muscles

• autonomic postganglionic neurons

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• NOT on preganglionic autonomic neurons

• neurons of brain

• adrenal medulla neurons

• receptor subtypes

• Nm - muscle

• Nn - neuron

• nicotine binds to these same sites - acts as ACh agonist

• complex reaction

• recording electrical activity of VTA neurons in midbrain slice —> nicotine activates, then  desensitizes nicotinic receptors

• recording electrode on brain slice

• nicotine initially has activation effect - increased depolarization

• when nicotine taken away, receptors become re-sensitized (sometimes hypersensitized) • nicotine application (subjected to continuous agonist exposure)

• nicotine activates, then desensitizes nicotinic receptors after short period of time • desensitization: altered state in which the channel is closed regardless of whether  molecules are bound to receptor

• nicotine removed to little immediate effect

• later, receptors resensitize spontaneously and are again capable of response • may make more receptors

• not all cells desensitized, and if active for too long —> depolarization block: resting  potential is lost and cell cannot be exited until agonist removed and membrane repolarized • succyinylcholine: muscle relaxant that is resistant to breakdown by AChE —>  desensitizes cell and causes depolarization block

• muscarinic

• metabotropic

• 5 types (m1-m5)

• stimulation of potassium channels, leading to hyperpolarization

• found in neocortex, hippocampus, hypothalamus and midbrain

• M5 has roles in midbrain dopaminergic cell activity and morphine reward • in striatum - involved in movement

• lots in cardiac muscles, smooth muscles  

• mediate secretory responses of ANS (salivation, crying)—> dry mouth when these are  blocked  

• parasympathomimetic agents: ingestion mimics parasympathetic activation (muscarine,  pilocarpine, arecoline)

• parasympatholytic agents: inhibit parasympathetic actions (atropine, scopolamine) • dilation of pupils

• acute effects

• cognitive

• arousal, alertness

• attentiveness

• relaxation

• enhances cognitive functions (attention and memory tasks improved)

• autonomic - mostly sympathetic effects (with exception of increase in GI activity) • increased respiration, heart rate, blood pressure

• suppressed appetite

• decreased diuresis

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Thursday, October 27, 2016

• increased GI activity - this parasympathetic activation caused by the fact that there are  site in both parasympathetic and sympathetic system that have nicotinic receptors • autonomic nicotinic receptors - on postganglionic neurons of sympathetic or parasympathetic • autonomic ganglia - Nn

• sympathetic activation

• parasympathetic activation

• acute toxic effects - 500 mg can be fatal (each cigarette has ~15 mg)

• dizziness, nausea, vomiting, tremor

• brain seizures (not as common)

• twitches and tremors

• respiratory suppression (see below)

• death

• chemical trigger zone (area postrema) can be accessed by nicotine and will cause  nausea/vomiting

• effects on muscles - skeletal muscles Nm (reacts at high doses)

• muscle nicotinic receptors have a lower affinity for nicotine, so these effects require  a lot of nicotine in the body

• muscle tremors

• muscle twitches

• respiratory suppression (2 ways)

• 1. inhibits medullary respiratory centers  

• these activate the dorsal respiratory group (DRG), then ventral respiratory group  (VRG)

• because they activate then desensitize, they contract it then shut them down • shuts down brain signals to breath

• 2. blocks contraction of respiratory muscles  

• DRG goes to external intercostal muscle and diaphragm

• VRG goes to accessory respiratory muscle and internal intercostal muscles • shuts down muscles

• therapeutic uses

• current: smoking cessation

• gum, mints, patches

• potential (not approved)

• depression

• schizophrenia - patients usually smoke frequently

• Alzheimer’s - involved with cholinergic neurons, so nicotine may activate the system  • Tourette’s

• ADHD

• anxiety  

• manduca sexta - tobacco caterpillars

• can release nicotine from pores and protect against wolf spiders

• insecticides

• nicotine has been used in many insecticides

• acute tolerance related to desensitization - goes away after a day of abstinence • chronic tolerance: up-regulation of nicotinic receptor expression

• factors in smoking addiction

• physical dependence

• tolerance development - amount needed increases

• withdrawal syndrome occurs upon cessation

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Thursday, October 27, 2016

• withdrawal period related to hyper-sensitization of receptors after the  

desensitization

• during smoking: activation —> desensitization (leads to craving)

• not smoking: hyper-sensitization

• smoking: activation….

• smoking saturates nicotinic receptors in the brain

• as nicotine attaches to nicotinic receptors, displaces radiolabeled tracer • nicotine from 3 puffs displaces 75% of tracer from study receptors

• nicotine from 3 cigarettes displaces almost all - 3 cigarettes completely cover all  the receptors

• unoccupied receptors induce withdrawal symptoms (not enough nicotine) • withdrawal symptoms

• irritability

• anxiety

• distraction

• restlessness

• insomnia

• hunger

• weight gain

• psychological dependence - positive reinforcement  

• dopamine reward system (VTA —> nucleus accumbens)

• nicotine causes release of dopamine in nucleus accumbens

• conditioning cues (more social in nature)

• sensory (taste, smell, touch) - negative reinforcement

• mood (arouses, relaxes)

• social (peer cues)

• health effects of chronic smoking

• 1200 people die each day from cigarette smoke

• annual premature deaths in US: smoking causes 430,000 (more than any other drugs, car  accidents, AIDS, murder, etc)

• mostly involve cardiovascular and respiratory system  

• bladder cancer correlated to smoking

• NOT the nicotine that’s causing most of these issues (other carcinogens and  chemicals)

• skin aging

• lung disease/cancers

• infertility

• incontinence

• urinary tract disease/cancer

• gum disease

• heart disease

• impotence

• poor blood clotting  

• over 4000 chemicals generated by burning tobacco - carcinogens

• the higher the temperature of burning, more you draw on it, the more chemicals you inhale • 69 cancer causing agents

• 11 are known human carcinogens

• 7 are probable

• 49 are known animal carcinogens

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Thursday, October 27, 2016

• causes high incidence of cancers

• lung, mouth, throat, stomach, bladder

• lung cancer spreads very quickly, causes death quickly

• effects of smoking on cardiovascular system

• increases demand

• increases heart rate and contraction

• increases blood pressure

• reduces oxygen supply to heart

• atherosclerosis - buildup of material within blood vessels

• carbon monoxide reduces affinity of hemoglobin for oxygen

• impairs pulmonary function

• chronic obstructive pulmonary disease (COPD) - emphysema, asthma, chronic  bronchitis

• bronchitis: inflammation/thickening of bronchial tube walls

• causes narrowing of tubes (diameter reduced), coughing spells occur

• can be reversible - if stop smoking, often goes away  

• emphysema:

• alveoli walls damaged by inflammation (not reversible)

• can lose natural elasticity, become overstretched and rupture

• adjacent ones may rupture at the same time, forming one large space instead of many  small ones

• usually causes death

• out of 20 people

• 5 will smoke

• 5 will try to quit

• 1 will quit, 4 will continue to smoke

• 1 in 4 smoker will die prematurely from smoking-related disease

• smoke because…

• image

• rebellion

• peer pressure

• stress relief

• weight control

• advertising

• 80% of smoking adults started before age 18

• each day 6000 youths smoke their first cigarette

• pharmacotherapy for smoking addiction

• nicotine replacement - occupies nicotinic receptors

• bupropion - antidepressant than backs dopamine reuptake

• varenicline - partial nicotinic receptors agonist

Caffeine  

• 80-90% of adults in US drink caffeine in some form

• basic pharmacology:

• oral administration - absorbed within 30-60 minutes

• absorbed mainly in small intestine

• average half life is 4 hours - mostly cleared from plasma during sleep

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Thursday, October 27, 2016

• rate of plasma clearance stimulated by smoking (this is why heavy coffee drinkers have  cigarette withdrawal quickly)

• methylxanthines

• caffeine: 3 methyls

• coffee, tea, chocolate, soda, drug preparations

• 100mg in coffee, 50 mg in tea, 40mg in soda, 10 mg in chocolate

• theobromine: 2 methyls

• chocolate

• theophylline: 2 methyls

• tea

• pharmacokinetics

• oral administration

• weak base absorbed by GI tract

• crosses BBB

• metabolized to paraxanthine, theobromine and theophylline

• half life = 4 hours

• biotransformation:

• metabolized to paraxanthine, theobromine and theophylline

• mechanisms:

• blockade of adenosine receptors (low doses)

• adenosine similar to neurotransmitters in function

• at low doses, methylxanthines block adenosine A2a receptors

• minor inhibitory transmitter

• A2a receptors are blocked by methylxanthine, causeing mild disinhibition of the  brain

• inhibits cAMP phosphodiesterase (which breaks down cAMP)

• inhibition of phosphodiesterase (high doses)

• blockage of GABAa receptors (high doses)

• increased calcium release at very high dosages

• acute behavioral and psychological effects

• increased arousal

• increased feelings of well being, vigor, self confidence, motivation, sociability, alertness • improved reaction, dexterity

• enhance cognitive function/athletic performance

• at high does - tension/anxiety

• acute physiological effects

• decreased blood flow to brain

• increased OR decreased incidence of migraines

• increased respiration rate

• dilated airways

• increased gastric secretions

• diuresis

• tolerance

• cellular tolerance: increased adenosine receptors

• behavioral tolerance: functioning in presence of drug

• contextual tolerance: context in which drug is taken induces tolerance

• dependence

• physical: headache, drowsiness, impaired concentration, mild anxiety/depression • if abstinence for a while, eventually symptoms go away

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Thursday, October 27, 2016

• psychological: weak reinforcer

• increases release of dopamine in cortex

• toxic effects:

• 500-1000mg

• anxiety/irritability

• insomnia

• fever

• flushing

• increased BP and heart rate

• >1500 mg

• paranoia

• delusions

• hallucinations

• stereotypies

• stimulations of catecholamine release from adrenal medulla

• therapeutic uses:

• headaches

• narcolepsy

• mild analgesic

• treatment of newborn infants with apnea - regulates their breathing

• asthma? type 2 diabetes?

• health risks?

• cancer - no clear association

• benign breast disease - increases sensitivity

• reproduction - fertility, miscarriage, growth

• cardiovascular - tachycardia, arythmie

• anxiety disorders - precipitates panic attacks

• physical dependence - withdrawal effects

• caffeinism: chronic ingestion of excessive caffeine

• restlessness, nervousness, insomnia, tachycardia, GI upset (similar to anxiety  disorder)

• caffeine use associated with lower risks of diseases

• diabetes (Type 2)

• cardiovascular

• liver disease

• Parkinson’s

• coffee contains antioxidants that are anti inflammatory

• caffeine consumption should be low to moderate (<3 cups/day)

• caffeine is present in ma

Opioids  

• narcotic analgesics: reduce pain without making you unconscious

• different from anesthetics, which depress CNS and make unconscious

• opium poppy - opium is dried milk from seed capsule

• paregoric: given to children in the past

• quiet the children and firm their stool

• slow intestinal activity

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Thursday, October 27, 2016

• Mrs. Winslow’s soothing syrup

• quieted restless infants and small children

• helped mothers relax

• opium smoking very popular in England, Japanese and Chinese immigrants to US • opioid agonists

• natural (derivatives derived from plant)

• morphine (10%)

• codeine (< 1%)

• thebaine (trace opioid)

• semisynthetic

• heroin (diacetylmorphine)

• hydromorphone (Dilaudid)

• osycodone (Percodan)

• ethorphine

• synthetic

• pentazocine (Dolophine)

• meperidine (Demerol)

• fentanyl (Innovar)

• methadone

• LAAM

• propoxyphene (Darvon)

• endogenous

• enkephalins

• endorphins

• dynorphins

• endomorphins

• criteria for classification as an opioid agonist

• exerts effects similar to morphine

• acts at opioid receptors  

• effects are blocked by naloxone (pure opioid antagonist)

• antagonists

• naloxone (Narcan)

• reverses effects of opioid agonists

• precipitates withdrawal in users

• used to reverse overdose

• naltrexone (Trexan)

• long acting form

• used to treat addictions

• therapeutic

• oral - synthetics, morphine, codeine

• IV, IM - synthetics, morphine (paraenteral)

• transdermal - fentanyl (patch bc lipophilic)

• non-therapeutic:

• paraenteral (IV, IM): heroin, morphine

• intranasal: heroin

• inhalation: opium, heroin

• heroin

• diacetylmorphine (morphine with 2 acetyl groups)

• more potent than morphine because  

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Thursday, October 27, 2016

• more lipophilic than morphine

• crosses BBB more efficiently than morphine

• heroin converted into morphine by brain enzymes

• created by Bayer

• aspirin: acetylsalicylic acid

• mechanisms

• typically depress activity in other neurons

• inhibitory neurotransmitters (inhibits at multiple levels)

• inhibits adenylyl cyclase via inhibitory Gi

• opioid agonist goes to Gi receptor, which inhibits adenylyl cyclase

• reduces cAMP formation

• postsynaptic inhibition (IPSP)

• at axosomal synapse

• opioids released onto postsynaptic mu receptors

• K+ channels open, K+ efflux

• hyperpolarization —> IPSP

• presynaptic inhibition - decrease transmitter release

• axoaxonal synapse

• presynaptic kappa receptors

• calcium channels close —> reduced nt release (other nt, such as Ach, NE, etc) • autoreceptor activation - decrease in transmitter release  

• corelease (opioid neurons release more than one neurotransmitter)

• presynaptic autoreceptors

• calcium channels close —> reduced transmitter release

• opioid bioassay: measures what drug/transmitter DOES to the cell

• bioassay: use of live animal or plant (in vivo) or in vitro (in vitro) to determined biological  activity of a substance

• conducted in guinea pig intestinal smooth muscle or mouse vas deferents smooth muscle • these contain opioid receptors

• electrically stimulate smooth muscle to cause action potentials

• followed by contraction (can measure shortening with transducer)

• can add drugs into vessel containing muscle strip

• opioids inhibit contraction (morphine)

• naloxone blocks opioid receptors, so morphine no longer has effect (contraction continues) • opioids cause constipation due to the fact that contraction in smooth muscles (intestines)  occur

• opioid receptors - metabotropic (ALL)

• mu (MOR)

• kappa (KOR)

• delta (DOR)

• discovery of opioid receptors (Pert and Snyder - 1973)

• tried to identify if natural opioid receptor in the body

• developed receptor binding assay - receptor binding measurement labels opioid receptors • used [3H] naloxone to label receptors

• tritiated naloxone - 2 tritiums off of C-C double bond

• identified opioid receptors in brain

• receptor binging measurement [3H] naloxone labels opioid receptors

• saturation plot

• Kd at the bottom (affinity)

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Thursday, October 27, 2016

• Bmax (all receptors filled)

• affinity of agonist for opioid receptors predicts inhibitory potency at smooth muscle • compares IC50 with ED50

• IC50 - number where 50% of receptors are displaced  

• vary concentration of agonists against competitors for the same receptors • ED50 - effective dose for 50%

• inhibitions of electrically induces contractions

• affinity of compound for opioid receptors predicts inhibitory potency at muscle • meperidine has lowest affinity (has highest IC50)

• etorphine has highest potency because lowest ED50

• 1000 more potent than morphine

• highly toxic in humans - used to immobilize elephants

• endogenous opioids:

• made up of amino acids

• peptide precursors

• 4 classes

• opioid agonists

• do NOT depolarize membranes

• discovery (Kosterlitz and Hughes - 1974) with bioassay of smooth muscles • stimulate guinea pig intestine muscle strip electrically and recorded smooth muscle  contraction

• applied brain extract (from pigs) to preparation

• recorded inhibition of contractions - BLOCKED contractions

• must have contained opioid receptors - brain extract acted just like morphine • first demonstration that brain made opioid-like compound

• contractions restored with naloxone

• next step: isolate endogenous opioids

• Kosterlitz and Hughes with pigs

• Pert and Snyder with calves

• met-enkephalin (5 amino acids strung together via peptides)

• first endogenous opioid peptide identified

• leu-enkephalin

• endomorphins: James Zadina (from Tulane!)

• high affinity and selectivity for mu receptors

• effects similar to morphine

• may be less dependence-forming

• analog must be developed (because cannot cross BBB due to peptide nature) • synthesis of opioid peptides: all come from larger molecules

• DNA transcribes long sequences of mRNA

• mRNA is translated into large precursor peptides

• enzymes cleave amino acid sequences for each peptide

Endogenous Opioid

Peptide Precursor

Preferred Receptor

endomorphin (4 aa)

unknown

mu

enkephalin (5aa)

proenkephalin

mu, delta

dynorphin (8-29aa)

prodynorphin

kappa

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Endogenous Opioid

Peptide Precursor

Preferred Receptor

endorphin (16-31 aa)

POMC

mu, delta

• precursors:

• pro-opiomelanocortin

• makes beta endorphins

• proenkephalin

• makes met-enkephalin and leu-enkephalin

• prodynorphin

• maybes dynorphin A

• opioid receptors in body

• brain  

• spinal cord

• intestine

• opioid receptors in CNS

• many areas related to different functional effects

• acute effects

• due to effects on cortex: sedation, drowsiness, relaxation

• euphoria (may involve mesolimbic DA pathway)

• medullary effects:

• pupillary constriction

• nausea, vomiting

• cough suppression

• respiratory suppression

• hypothalamic effects:

• hypothermia

• reduced sex drive

• intestinal effects: analgesia

• mu receptors are IN the intestines

• opioids bind to mu receptors and inhibit intestinal motility

• ascending pain systems

• opioid neurons all throughout the ascending pain path (from peripheral nerves to cortex  where pain is perceived)

• at medulla, spinal cord, pons, midbrain, thalamic nuclei, etc.  

• opioids try to reduce the pain

• opioids induce analgesia at multiple CNS sites

• spinal analgesia - inhibition of pain sensation

• brainstem analgesia - inhibition of pain sensation

• limbic, thalamic and cortical analgesia - inhibits pain perception

• how do you feel about the pain

• toxic effects:

• respiratory suppression

• opioid receptors in the medulla - opioids inhibit respiratory signals from medulla to  lungs

• pontine respiratory centers

• pons

• ventral/dorsal respiratory groups

• signs of opioid overdose

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• deep, slow snoring/gurgling

• heavy nod, not responsive to stimuli

• slowed breathing

• cyanotic-bluish lips and nail beds

• pinpoint pupils (very small)

• therapeutic uses:

• analgesic

• cough suppression

• anesthesia (fentanyl)

• fentanyl also used as analgesic - is currently a problem with overdose

• more people are dying from fentanyl or heroin overdose than from murder • substance abuse tx

• reduce intestinal motility

• opioid tolerance:  

• not the same for all effects

• rapid for analgesic effects, slower for constipating effects

• cross tolerance between different opioids

• mostly based on changes in nerve cells that compensate for the presence of chronic  opioids (cellular tolerance)

• cellular (pharmacodynamic) tolerance - cell does opposite of drug effects • decrease in opioid receptors  

• increase in adenylyl cyclase

• contextual (situational) tolerance

• context in which drug is taken changes the tolerance

• experiment:

• 15 heroin injections —> test injection in same room —> 30% dead - tolerance • 15 heroin injections —> test injection in different room —> 65% dead - less tolerance • no heroin injections —> test injection —> 95% dead - no tolerance

• sensitization: increases in drug effects that occurs with repeated administration • ***tolerance and dependence are INDEPENDENT!!!***

• physical dependence:

• withdrawal syndrome (not life-threatening)

• opposite of acute effects

• rarely life-threatening (just feel terrible)

• 1-2 weeks in duration

• detoxified: abstinence signs ends

• acute vs. withdrawal effects (opposite)

Acute

withdrawal

hypothermia

hyperthermia

decreased bp

increased bp

peripheral vasodilation

piloerection

skin flushing

chills

miosis (constriction)

madrases (dilation)

drying of secretions

eyes and nasal secretion

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Thursday, October 27, 2016

Acute

withdrawal

constipation

diarrhea

respiratory suppression

yawning, panting

antitussion

coughing, sneezing

decreased libido

spontaneous orgasms

relaxation

agitation, resltessness

analgesia

pain

euphoria

dysphoria, depression

• psychological dependence

• powerful reinforcer - self-stimulation with animals  

• the threshold for current is lowered with opioids, indicating that the drugs enhance the  reward system

• intense craving, rush

• increase release of DA in accumbens

• probably too simple a model

• route of administration affects development of dependence

• faster the route of administration, more likely to become dependent

• IV heroin most addictive, the snorted heroin, morphine, methadone (oral), LAAM (oral -  treats opioid addiction)

• coca leaves —> paste —> cocaine —> crack

• nicotine patch —> snuff —> cigarettes (inhalation)

• more addictive = faster speed of onset = shorter duration of action

• treatment not just detoxifying, need to take into account bx and social factors • electroacupuncture

• detoxification is first step

• can reduce withdrawal with small amounts of methadone (long-acting), clonidine (agonist  at a2-adrenergic receptors)

• drug therapies for opioid dependence

• methadone maintenance program

• full opioid agonist  

• administered every day

• mild opioid effects  

• ORAL administration (usually liquid), which reduces euphoria  

• methadone sits on receptors, which may reduce cravings

• reduces effects of heroin and morphine

• withdrawal from methadone is much less intense

• long-acting, which produces more constant blood level  

• passes placental barrier, so children may have issues

• most common

• hazards: accidental overdose at beginning of treatment (methadone has long half life) • buprenorphine

• partial agonist at mu receptors (high affinity but low efficacy)

• typical opioid effects but milder

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• also used as analgesic

• longer duration of action, so only needs to be administered 1-3 times per week • very mild withdrawal symptoms

• sublingual

• reduced overdose risk

• reduces intensity of withdrawal

• naltrexone

• pure opioid antagonist (long-term naloxone)

• blocks receptors, so opioids can’t access receptors (rendered ineffective) • precipitates withdrawal in users

• can take orally

• need a lot of motivation to volunteer - cravings are not eliminated

• blocks life-threatening effects

• vaccines:  

• produce antibodies that bind to drug in circulation and prevent brain entry • clonidine

• administered when in physical withdrawal  

• noradrenergic alpha autoreceptor agonist

• reduces NE release

• suppresses physical withdrawal symptoms during week of withdrawal

• mixed preparations - various combinations under study

Tolerance and Dependence

• evolution of US drug laws

• Harrison act 1914: regulated dispensing and use of opioid drugs and cocaine • one of the first drug laws

• largely because racial issues (opium related to Chinese)

• eventually this law was extended to ban other drugs

• prohibition 1920

• marijuana tax act 1937

• controlled substances act 1970

• current US drug schedules

• established by comprehensive drug abuse prevention and control act 1970 • I - no accepted medical use and high abuse potential

• heroin, LSD, THC, MDMA

• II - high abuse potential with severe psychic or physical dependence liability • opium, morphine, cocaine, amphetamine

• III - moderate abuse potential

• ketamine, codeine

• IV - mild abuse potential

• Valium, Xanax, benzodiazepines

• V - low abuse potential

• buprenorphine

• drug use in US in 2013

• 9.4% over age 12 used illicit drugs in the past month

• DSM-V - Substance Use Disorder (requires 2 of the following within a 12-month period) 27

Thursday, October 27, 2016

• 1. the substance is often taken in larger amounts or over a longer period than was  intended.

• 2. there is a persistent desire or unsuccessful effort to cut down or control use of the  substance.

• 3. a great deal of time is spent in activities necessary to obtain the substance, use the  substance, or recover from its effects.

• 4. craving, or a strong desire or urge to use the substance.

• 5. recurrent use of the substance resulting in a failure to fulfill major role obligations at  work, school, or home.

• 6. continued use of the substance despite having persistent or recurrent social or  interpersonal problems caused or exacerbated by effects of its use.

• 7. important social, occupational, or recreational activities are given up or reduced  because of use of the substance.

• 8. recurrent use of the substance in situations in which it is physically hazardous. • 9. use of the substance is continued despite knowledge of having a persistent or recurrent  physical or psychological problem that is likely to have been caused or exacerbated by the  substance.

• 10. tolerance, as defined by either of the following:

• a need for markedly increased amounts of the substance to achieve intoxication or  desired effect.

• a markedly diminished effect with continued use of the same amount of the substance. • 11. withdrawal, as manifested by either of the following:

• the characteristic withdrawal syndrome for that substance (as specified in the DSM- 5  for each substance).

• the substance (or a closely related substance) is taken to relieve or avoid withdrawal  symptoms.

• 3 major models:

• 1. physical dependence model (Wikler)

• physical dependence —> attempts at abstinence

• —> withdrawal symptoms occur, which causes relapse

• worst physical withdrawal occurs with alcohol and heroin

• 2. positive reinforcement (Koob)

• reinforcement causes compulsive desire to re-experience drug-induced euphoria • many drugs of abuse increase DA release in nucleus accumbens (mesolimbic pathway) • VTA (cell bodies)—> NA (axon terminals)

• nucleus accumbens axon terminals synapse on other neurons in the nucleus  accumbens

• worst reinforcement occurs with cocaine, amphetamine and heroin

• self-administration paradigm  

• rodents self-administer drugs of abuse at high rates (especially if unenriched  environment)

• cocaine and amphetamines the highest rate (heroin also high, but depressant so they  slow down a bit)

• conditioned place preference paradigm

• determine pre-drug compartment preference (leave door open to allow it to choose) • condition non-preferred side to test drug

• condition preferred side to vehicle control

• test post-conditioning preference without drug

• —> rodents prefer drug compartment

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• drugs of abuse increase synaptic dopamine in nucleus accumbens

• cocaine

• amphetamine

• nicotine

• morphine

• 3. incentive-sensitization (Robinson)

• taking drug repeatedly causes sensitization of drug “wanting” but not drug “liking” • euphoria from drug plateaus/lessens, but cravings/wanting increases(original effect is  never as strong as the initial time)

• attempts at abstinence are followed by compulsive desire for the drug due to a sensitized  incentive salience system

• this is moderated by dopamine

• psychostimulant dependence

• rodents prefer compartment paired with cocaine (in conditioned place preference) • after conditioning, animals prefer drug paired compartment

• eventually, preference goes extinct and go back to baseline levels (10 days post conditioning)

• micro dialysis experiment: cocaine induces dopamine release in NA

• higher dose of cocaine = higher levels of dopamine

• animals in enriched environments showed no difference

• methylphenidate induces NE and DA release in nucleus accumbens

• has a stronger effect in the cortex - not as strong in the nucleus accumbens (leads to  lower risk of abuse)

• mesolimbic dopamine pathway: VTA —> NA

• cocaine blocks DA reuptake in NA - more dopamine left in synaptic cleft • amphetamine stimulates DA release in NA - more available dopamine in synapse • dendritic remodeling in nucleus accumbens  

• after repeated drug exposure, increased spines on NA neurons (receiving dopamine  from VTA)  

• use-dependent plasticity leading to sensitized responses to drug

• mainly used with psychostimulants, but has been extended to other drugs • ΔFosB: transcription factor (protein) that regulates gene expression

• stable protein that stays around for months

• accumulation after repeated exposure to cocaine restructures NA

• stimulates gene expression leading to dendritic restricting in NA

• this increases sensitivity of dopamine reward pathway

• makes more spines

• acute: rises faster

• chronic: rises slowly with accumulating ΔFosB

• accumulates after either self-administration of experimenter admin.

• repeated drug administration —> gene expression (via transcription factor delta FosB) • —> dendritic remodeling

• —> drug addiction

• nicotine dependence

• DA release in nucleus accumbens after injection (via micro dialysis tube) • after low dose, smaller peak

• after high dose, HUGE peak

• mesolimbic pathway

• ACh cell bodies synapse ONTO dopamine neurons

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• laterodorsal tegmentum (LTD) and peripeduncular tegmentum (PPT)

• project to VTA via cholinergic neurons (end on nicotinic receptors)

• nicotine acts at nicotinic receptors on VTA neurons to stimulate release of DA in NA • also send dopamine to PFC (arousal)

• ACh neurons in LDT and PPT project onto nicotinic receptors on dopaminergic neurons in  VTA

• this sends DA from the VTA to the PFC and nucleus accumbens

• opioid dependence

• 2 methods to determine neurobiology

• self-administration of opioid ligands

• selective lesions

• support self-administration and conditioned place preference

• rats will continue to prefer compartments paired with morphine

• morphine induces dopamine release in nucleus accumbens

• opioids inhibit GABA neurons in VTA (acute)  

• this disinhibits DA neurons in VTA (via inhibition of inhibitory GABA neurons) • may open K channels or reduce Ca influx

• leads to increased DA release in NA

• agonists produce opposite effects - may mediate averse effects

• postsynaptic inhibition

• postsynaptic receptors —> K+ channels open with K+ efflux

• —> hyperpolarization

• —> IPSP (on GABAergic neurons)

• presynaptic inhibition (axoaxonal)

• opioid synapses on axon of GABA neuron

• presynaptic receptors —> calcium channels close

• —> reduced transmitter release onto dopaminergic neurons

• —> more dopamine released onto nucleus accumbens

• contradictions in the evidence supporting the role of dopamine in drug use and abuse • dopamine in the NA may regulate psychostimulant “wanting” but not “liking” • some drugs induce release of dopamine in the NA but are not abused • narcolepsy drug

• early studies on the ability of opioids to induce release of dopamine suffered from low  sample size and small effects (fit well with other data)

• simplicity of the dopamine reward hypothesis encouraged its non-critical acceptance

Hallucinogens  

• aka psychedelics or psychomimetics

• diverse assortment of compounds

• alter various neurotransmitter systems

• variety of effects on physiology and behavior

• alter sensation, mood, perception, thinking, memory and movement (can be positive or  negative effects)

• witches’ brew: mainly hallucinogenic drugs (psychedelic effects)

• types of hallucinogens

• serotonergic

• monoaminergic

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• glutamatergic

• cannabinoid

• serotonin (classic psychedelics)

• monoamine - indoleamine

• involved in appetite, sleep, pain, mood, depression, anxiety

• synapse

• 5-HT packaged into vesicles

• reserpine:

• 5-HT autoreceptor

• SSRIs

• synthesis:

• L-Tryptophan —> L-5 hydroxytryptophan (5-HTP)  

• via tryptophan hydroxylase (adds OH group)

• —> 5-hydroxytryptamine (5-HT - serotonin)

• via aromatic L-amino acid decarboxylase (AADC) - removes COOH

• degradation

• serotonin —> 5-hydroxyindole acetaldehyde

• via monoamine oxidase

• —> 5-hydroxyindoleacetic acid (5-HIAA)

• via aldehyde dehydrogenase

• important measure in mental disorders

• serotonergic system

• Raphe nuclei (B1-B9) —> many areas

• serotonergic cell bodies project diffusely throughout brain and spinal cord • serotonergic hallucinogens: very similar in structure to serotonin, analogous regions • lysergic acid diethylamide (LSD)- synthetic

• dimethyltryptamine (DMT)- plant derivative

• found in ayahuasca (yage)

• bufotenine - plant and animal derivative

• toad skin

• not similar in structure to serotonin like the others

• psilocybin, psilocin - plant derivative  

• found in mushrooms

• psilocin is the active metabolite

• receptor mechanisms of action of serotonergic hallucinogens

• LSD binds to many different 5-HT subtypes

• probable targets are 5-HT2A subtypes

• 5-HT2A antagonists block serotonin syndrome

• 5-HT2A antagonists block perceptual effects

• 5-HT2A affinity predicts hallucinogenic potency

• tolerance linked to 5-HT2A receptors decrease

• conclusion: serotonin psychedelics are 5-HT2A agonists

• serotonin receptors

• 5-HT2A agonists block perceptual effects of psilocybin

• 5-HT2A affinity of hallucinogens predicts hallucinogenic potency

• serotonergic hallucinogens may disrupt activity of cortical pyramidal neurons causing  perceptual and cognitive alterations

• lysergic cis diethylamide (LSD)

• usually oral administration, typical does is 50-100 micrograms

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Thursday, October 27, 2016

• ergot, lysergic acid produces by fungus growing on grain

• LSD-25, synthetic version of ergot synthesized by Hoffman in 1938

• effective at microgram doses, 1% reaches brain

• effects begin 30 minutes, persist for 6-12 hours

• mild to strong sympathomimetic effects

• headache, nausea, vomiting, tremors, dizziness, muscle weakness

• mild toxicity, not lethal

• increases risk behaviors

• hallucinogenic effects

• cognitive: lucid thinking, unique perspectives

• esthetic: sensory effects, hallucinations, synesthesia

• psychodynamic: reduced stress, repressed emotion

• transcendental: unity, transcendence of space and time

• psychotic: fear, panic, confusion, delusions, depression

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