study worksheet 2

7/28/2019 Study Worksheet 2

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Drug Drug of abuse

used to treat

Receptor(s) acted

upon

Mechanism of action

(full/partial

direct/indirect agonist,

antagonist, etc)

Notes (What aspects of drug use does it tr

Side effects, etc)

Modafinil Cocaine, post-

chemotherapy

cognitiveimpairment,

methamphetamine

, other stimulants

Catecholamines,

serotonin, glutamate,

histamine, GABA,orexin, hypocretin

full indirect agonist (DA

reuptake inhib. &

catecholamine reuptakeinhib.)

Stimulant dependent. Improves cognitiv

performance in healthy participants. Impr

performance of MA-dependant subjectsreversal learning task. Boosts brain activit

executive cntrl regions. Double-blind

placebo-controlled trial of modafinil (40

mg/da) for MA-dependence = no sig.

improvements in treatment

retention/abstinence from MA in full sam

(one size does not fit all!). Better

retention/abstinence for subjects w/ hig

(>18da/mo) MA-dependence before begin

treatment.

Methadone Heroin, morphine,

& similar drugs.

Treatment for

opioid

dependence;

however, also

highly addictive.

Glutamate, Partial agonists. Opioid dependence. The Dole-Nyswand

Legacy (methadone maintenance therap

MMT): view heroin addiction as a medic

treatable disease; use the synthetic opio

agonist methadone to treat heroin addicti

Longer -life than heroin (thus, less

withdrawal), can be admin. daily, preven

withdrawal/craving, produces tolerance

allows relatively normal life. MMT is

controversial (trading one addiction fo

another?): heavily regulated, by law a

physician CANNOT prescribe methadon

tx opioid withdrawal fr. office, any M.D.

DEA# can prescribe for pain. Analgesi

maintenance therapy for opioid dependen

long action. Developed in Germany in 19

Acts on same opioid receptors as morphiw/ many the same effects. Intro. into US

1947. Cross-tolerance w/ other opioids

including heroin & morphine. Oral doses

mitigate (lessen) opioid withdrawal syndr

Higher doses block euphoric effects of he

morphine, & similar drugs.

Nicotine

replacement

Nicotine Full direct agonists Cigarette smoking. Ex: the nicotinic pat

(Murray E. Jarvik, Jed E. Rose, & K. Dan

Rose). Nicotine Replacement Therapy

transdermal=nicotine patches, oral=gum

nasal= spray, inhaler.

Methylphenidate Full indirect agonist

Buproprion (aka.

Wellbutrin, Zyban)

nicotine NE, DA Full indirect agonist (NE

& DA reuptake inhib.),

nAChR antagonist.

Stimulant dependence, cigarette smoking

cholor-N-tert-butyl--ketoamphetamine

substituted amphetamine. Binds selective

DA transporter (but behave. effects b/c in

NE reuptake). Initially marked as

antidepressant. Later found to be effective

smoking cessation aid.


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Buprenorphine Opioids, treatment

for opioid

dependence.

(However, also

produces

dependence).

Partial agonist:

likelihood of

overdose/respiratory

depression

(like methadone)

suppresses opioid

craving & withdrawal,

blocks effects of self-

admin opioids, treatment

retention, illicit (not

permitted) opioid use.

Opioid dependence. (discovered in 1966)

marketed in 1980s as an analgesic. Used

cntrl moderate-acute pain (low dosage

approx. 200g). Used to cntrl moderat

chronic pain (20-70 g/h). In 2002, FD

approved high-dose sublingual buprenorp

for detox & long-term replacement therap

opioid dependency (now used mainly for

purpose, >2mg). B/c is a partial agonis

maintains patients in a mild degree of phy

dependence & is associated w/ mild

withdrawal syndrome following cessati

(stopping drug abuse).

Varenicline

ore effective than

RTs (nicotinic

placement

erapies) formoking cessation.

nicotine 42, 34, 32,

7, &6 nAChRs

Partial agonist (at 42

nAchR), Full agonist (at

7-receptors)

Cigarette smoking. Weak action on 32&

containing nAChRs. Stimulates the 4

receptor but does not produce a full effect

nicotine. Does not greatly incr. the

downstream release of DA. Blocks the ab

of nicotine to bind/stimulate the mesolim

DA system (akin to action of buprenorphin

treatment of opioid addiction). Also actsagonist at 5-HT3 receptors (may contribu

mood altering effect of varenicline).

Aripiprazole Partial agonist (D2 &

5HT1A receptors)

Stimulant dependence.

Naloxone Heroin/morphine

OD.

Note: treatment of

heroin OD = O2

& naloxone (IV)

& monitoring

vital signs.

Extremely affinity

for receptors (in

ventrolateral

medulla), affinity

for - & -opioid

receptors.

Commonly called

receptor antagonists,

actually inverse agonists.

(aka. Narcan, Nalone, Narcanti) Devolope

1960s. Naloxone IV begins acting withi

minute. Distributed in emergency OD

response kits to heroin & other opioid dr

users ( the rates of fatal OD). CDC estim

take-home naloxone & training on using

reversed 10,000 opioid OD deaths.

-Experimental use to treat:

Congenital insensitivity to pain w/anhydrosis: extremely rare (1:125 millio

person does not feel pain.

Depersonalization disorder (dissociat

disorder): subjective experience of unre

in ones sense of self.

-In combination w/ opioid agonist drug

1. with oxycodone to prevent opioid-indu

constipation in patients requiring opioi

therapy.

2. with buprenorphine (Suboxone) in

maintenance therapy for opioid dependen

(+) Naloxone

(aka. Dextro-naloxone)

Morpoine/heroin

& other opioiddrugs

TLR4 Selective antagonist of

Toll-like receptor 4(TLR-4).

The unnatural enantiomer of (-)-naloxo

Unline (-), (+) has no sig. affinity for opireceptors. Selective antagonist of TLR-

TLR-4: involved in immune-sys respon

Activation of TLR-4 induces glial activa

& release of inflammatory mediators (e

TNF- & Interleukin-1). (+) used to blo

addiction via immune sys of the brain, w

targeting brains wiring; prevents craving

opioid drugs. Opioid drugs bind to TLR4

similar way to normal immune response


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Note: (-)-Naloxone:

bacteria (problem is TLR4 acts as amplif

for addiction).

(+) suppresses opioid-induced CPP an

reduced opioid self-adim in rats.

Naltrexone

or

Dosage Forms:

altrexone tabletsmay drop out early,

craving can be

leviated w/ opiate.

dropout w/

supervised tablet

aking, incentives,

sustained-release

naltrexone.

Can also take

naltrexone via

injection (higher

osage, less likely to

drop out.

Prevent relapse.

Blocks heroin

effects. Treatmentfor alcohol

dependence.

Commonly called

receptor antagonists,

actually inverse agonists.

(Maintenance after detox.). Long-actin

inverse agonist, used to prevent relapse

opioid dependence. Works best for highmotivated people.

Used in rapid detox:

- principle: to induce opioid-receptor bloc

while patient is in state of impaired

consciousness, to attenuate withdrawal

symptoms.

- Under general anesthesia (ultra-rapid

detox): requires intubation & ext. ventila

- Also possible under light sedation.

Rapid detox followed by oral nealtrexo

daily for up to 12 mo. (also can use naltrex

implant in lower abdomen).

Scientific disagreement to safety of procedas well as if should be performed under l

sedation/general anesthesia due to rapid

severe withdrawal that occurs. Often

misrepresented as a cure for opioid

dependence. Rapid detox criticized fo

questionable efficacy in long-term opio

dependence management.

CONS: no clear evidence of efficacy o

maintenance treatment, poor compliene

receptor sensitization may risk of death

opiate OD w/ cessation of naltrexone

treatment & relapse into addiction.

In Russia, substitution therapy forbidden, option is naltrexone. Due ot lack of alterna

& stronger family cntrl of compliance

(adherence), naltrexone more effective f

relapse prevention & abstinence stabiliza

in Russia than in Western countries.

Naloxone + Buprenophine =

Suboxone/Subutex (sublingual/sublingu

tablet): discourages i.v. abuse & diversio

patients dependent on full -opioid agon


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Precipitates withdrawal in opiate-depend

users.

Also treats alcohol dependence: in anim

opiate antagonists alcohol preference

(particularly in strains bred for excessiv

alcohol/after envir. Stressors that elici

excessive drinking). In humans, naltrexo

may reinforcing or pleasurable effects

alcohol in social drinkers & in alcohol

dependent subjects who slip. Thus, dat

suggests opioid antagonism may have

important pharmacological effects of t

reinforcing effects of alcohol & likeliho

of returning to clinically sig. drinking

Mech: (Opioids can induce DA release v

disinhib. of inhib GABAergic tone).

Naltrexone blocks pleasant & reinforcin

effects of alcohol by preventing stimulatio

opioid receptors, DA release in VTA

Suboxone Naloxone + Buprenophine =

Suboxone/Subutex (sublingual/sublingutablet): discourages i.v. abuse & diversio

patients dependent on full -opioid agon

Precipitates withdrawal in opiate-depend

users.

Flumazenil BZ OD. GABA-A receptors GABA antagonist (only

benzodiazepine (BZ)

receptor antagonist on

the market)

Antidote in treatment of BZ OD. Revers

effects of BZs by competitive inhib at B

binding site on GABA-A receptor.

Is one of the ingredients of Prometa (a

controversial treatment protocol used

primarily for METH addiction, claimed t

effective for alcohol & cocaine dependen

Disulfuram Inhibits ethanol

metabolism.

Reduces alcohol

& cocaine use.

Catecholamines,

acetaldehyde, DA,

NE.

Enzyme inhibitor - Inhibits ethanol metabolism.

Mech: Ethanol is converted into acetaldeh

by alcohol dehydrogenase (ADH).

Acetaldehyde is then transformed into ace

by aldehyde dehydrogenase (ALDH)

Disulfiram inhibits ALDH ( acetaldehy

Produces the disulfiram-ethanol rxn th

promotes abstinence from alcohol.

- Inclinical trials, disulfiram both alcoho

cocaine use. Later shown that disulfiram

cocaine use independent of an action o

alcohol consumption.

Mech: Disulfiram DA levels.In thecatecholamine syn. Pathway, tyrosine

converted to 3,4-dihydroxy-L-phenylalan

(L-DOPA) by tyrosine hydroxylase (TH

which is then transformed into DA by

aromatic aa decarboxylase (AADC). DA

hydroxylase (DBH) then converts DA in

NE. Disulfiram inhibits DBH, NE

production & ratio of DA:NE.


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How can DBH inhib. by disulfiram redu

cocaine use? (DA replacement therapy:

rewarding effects of cocaine, aversiv

affects of cocaine. Favored hypothesis

Decreased levels of NE mediate relaps

prevention.With NE, excitatory driv

VTA would result in extracellular Ddespite a higher DA level. Possible mec

Disulfiram effect on cocaine addiction

Vigabatrin Treats stimulant

dependence.

GABA GABA analogue,

enzyme inhibitor.

An antiepileptic drug that inhib. the

catabolism of GABA by irreversibly

inhibiting GABA transaminase. GABA

analogue, but not a GABA receptor agon

Some positive findings in treating stimul

dependence. Produces visual field defec

Cholinesterase

inhibitors

Cognitive

Function

ACh Enzyme inhibitor. Galantamine, Rivastigmine, Donepezi

Improved sustained attention in cocaine u

(Physostigmine, Rivastigmine). Attenuasubjective effects of amphetamines. Clin

trials have not yet shown reduced use o

stimulants.

Acomprosate

Ondansetron

Topiramate

Drug Short-term

side effects

Long-term

side effects

Receptor(s)

acted on,modulation

(excitatory

= +,

inhibitory

= -)

Receptor

compositionand

stoichiometry

Important

subunitsand their

function

Notes:

Nicotine

=liquid soluble plant

alkaloid, half-life of 2

Blocks

withdrawal.

Desensitizes

nicotinic

acetylcholine

(+) nAChR Pentamers,

assembled

from various

nAChR

subunits

encoded

Specific agonist at ion

channels normally gated

by Ach (called neuronal


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hrs in bloodstream,

reaches brain in 10

sec, metabolism rate:

depends on gender,

genetic factors, age,

ethnicity, mode of

ingestion. Come from

flower nicotiana

tabacum. Principal

breakdown product is

cotinine.

receptors.

Addictive &

very toxic

(LD50 0.1

mg/kg in

childen). &

other long-

term

physiological

alterations.

Induces

behave.

tolerance,

sensitization,

dependence,

&

withdrawal.

combinations

of proteins

encoded by

different

genes.

by 17

different

genes.

nicotinic Ach receptors,

nAChRs). In vertebrates,

17 different genes encode

nAChR subunit proteins. 5

subunits, 4 genes:

(1)2

Note: A fxnal receptor of

defined composition &

stoichiometry = subtype.

How nicotine works?

Release of NT DA in

mesolimbi sys of brain

mediates reinforcing

properties of several drugs

of abuse, including

nicotine. When

administered systemically

incr EC levels of DA in

dorsal & ventral NAcc

striatum by acting on

nAChR located on DAcell bodies and/or nerve

terminals. Accordingly,

lesionso of mesolimbic

DA neurons attenuate

nicotine self-admin in rats.

Transgeneic mice

establish a role for

nAChRs in reinforcing

properties of nicotine (2

subunit of nAChRs). 2-/-

mice extinguish self-

admin behavior when

nicotine is substituted forcocaine (compared to WT,

or self-admin nicotine

after trained to self-admin

cocaine).

Rewarding effects

attenuated thru VTA. 4-

containing nAChRs

mediate rewarding

properties of nicotine.

Low dose nicotine causes

nAChR fxnal up-regulatio

in L9Ala mice.

Behav. Test to studymotivational properties of

nicotine & other drugs is

CPP. Based on CPP assay,

0.5 mg/kg nicotine is

rewarding for WT mice.

Based on CPP assays, 4-

containing nAChRs are

sufficient for the

rewarding properties of


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nicotine. Most adult

smokers start smoking

during their adolescence.

Smoking cessation rates

of 7-20%. Smokers who

acquire insular damage

more likely to quit

smoking easily &

immediately and to

remain abstinent (no

longer experience

conscious urges to smoke

after quitting).

Alcohol K+

voltage-

gated ion

channelsm

GABAAR,

GlyR,

P2X.

Inhallentstoluene

InhallentsN20

Notes:

- Running Wheel Exercise Ameliorates METH Damage to DA and 5-HT Terminals (slide 13, 1stlecture of 6th week)

study worksheet 2

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