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TULANE / NSCI / NSC 4530 / psychopharmacology study guide

psychopharmacology study guide

psychopharmacology study guide


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

Thursday, October 27, 2016

what is the meaning of catecholamine synthesis?

Exam 2


• 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


• **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


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


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


Thursday, October 27, 2016

• 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  


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


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


• **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


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)


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


Thursday, October 27, 2016

• 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)


Thursday, October 27, 2016

• 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


Thursday, October 27, 2016

• 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)


• nicotiana tabucum: tobacco leaves

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

• cigarettes


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


Thursday, October 27, 2016

• 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


Thursday, October 27, 2016

• 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


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


• 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


Thursday, October 27, 2016

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


• 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


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


• 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


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


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


• 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


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


• 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  


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)


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)



enkephalin (5aa)


mu, delta

dynorphin (8-29aa)




Thursday, October 27, 2016

Endogenous Opioid

Peptide Precursor

Preferred Receptor

endorphin (16-31 aa)


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


Thursday, October 27, 2016

• 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)





decreased bp

increased bp

peripheral vasodilation


skin flushing


miosis (constriction)

madrases (dilation)

drying of secretions

eyes and nasal secretion


Thursday, October 27, 2016





respiratory suppression

yawning, panting


coughing, sneezing

decreased libido

spontaneous orgasms


agitation, resltessness




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


Thursday, October 27, 2016

• 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


Thursday, October 27, 2016

• 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


Thursday, October 27, 2016

• 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


• 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


Thursday, October 27, 2016

• 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


• 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


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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