study worksheet 2
TRANSCRIPT
-
7/28/2019 Study Worksheet 2
1/7
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.
-
7/28/2019 Study Worksheet 2
2/7
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
-
7/28/2019 Study Worksheet 2
3/7
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
-
7/28/2019 Study Worksheet 2
4/7
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.
-
7/28/2019 Study Worksheet 2
5/7
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
-
7/28/2019 Study Worksheet 2
6/7
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
-
7/28/2019 Study Worksheet 2
7/7
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)