drugofabuse drugs of abuse abuse...
TRANSCRIPT
Drugs of
Abuse
Jen-Hsin Kao Ph.D.
Drug of Abuse
Abuse Addiction
Drug of Abuse
Abuse Addiction
Drugs usedinwaysthatarenotmedicallyapproved
Drug of Abuse
Abuse Addiction
achronic,relapsing braindiseasethatcauses
compulsivedrugseekinganduse
Drug of Abuse
Abuse Addiction≠
Drug of Abuse
Abused
Drugs
Addictive
Opioid
Cannabinoids
GHB
Nicotine
Alcohol
Cocaine
Amphetamine
Not
Addictive
Hallucinogens: LSD
Ketamine&PCP
MDMA
Hypnotics:BZD&Barbiturates
DependenceSo-called ‘Physiologicaldependence’
Withdrawal syndrome
Addiction
So-called ‘Psychologicaldependence’
Inducestrongfeelingsofeuphoria andreward
Compulsivedruguse
Relapse
Craving, drug seeking
Dependence vs. Addiction The Reward Circuit
NAc
Nucleus accumbens
VTA
Ventral tegmental area
�Mesolimbic DA pathway
Nature highs
Behaviorally-inducedhighs
Substance-inducedhighs
DA
ClassificationofDrugsofAbuse
Based on their moleculartarget
GPCR Ion channel
Amine
transporter
ClassificationofDrugsofAbuse
Based on their moleculartarget
GPCR
Opioids
Cannabinoids
Gamma-hydroxybutyric acid(GHB)
Hallucinogens: LSD,mescaline,andpsilocybin
GPCR Nature Highs
Endogenous
opioids
PKA
cAMP
Target proteins
ATP
AC
Gi/o
NAc
VTA
VTA
NAc
GABA
neuron
GABA
neuron
DA
neuron
DA
GABA
receptor
Mesolimbic DA Pathway
Disinhibition
GPCR
NAc
VTA
VTA
NAc
GABA
neuron
GABA
neuron
DA
neuron
endogenous/exogenousopioid
DA
GABA
receptor
DA
Opioid Addiction
Reward
Disinhibition
MOR
Gi/o
GPCR
rhinorrhea lacrimation yawning chills
gooseflesh hyperthermia mydriasis muscular aches
vomiting diarrhea anxiety hostility
Withdrawal
syndrome
of
opioids
Opioid Dependence
= Physiologicaldependence
GPCR
Dose
Response
Full agonist
Partial agonist
Antagonist
Morphine
Heroin(→morphine)
Codeine
Oxycodone
Meperidine
Abused
μ-Opioids
Naloxone μ antagonist
Reverses opioid overdose
Precipitated withdrawal symptom
Methadoneμ agonist
(long half-life) Substitutiontherapy
ê Opioid withdrawal symptoms
Buprenorphine Partial μ agonist
Treatment:
GPCR Treatment of Opioid Addiction
Endogenous
cannabinoids
neurotransmitters
include 2-AG (2-arachidonylglycerol)and anandamide
bindatpresynaptic CB1receptors
Exogenous
cannabinoids
Δ9-THC (Δ9-tetra-hydrocannabinol) fromMarijuana
powerfulpsychoactive substance
cause euphoria, relaxation & hallucinations
é appetite
ê nausea(dronabinol)
reliefofchronicpain (Nabilone)
CannabinoidsGPCR
NAc
VTA
VTA
NAc
GABA
neuron
GABA
neuron
DA
neuron
cannabinoids
CB1
DA
GABA
receptor
DA
Cannabinoids Addiction
Reward
Disinhibition
Gi/o
GPCR Gamma-hydroxybutyric acid (GHB)GPCR
GABA
GHB
Inhibitory neurotransmitter
Binds to GABAA& GABA
Breceptor
apopular"clubdrug”
Bind to GABABreceptor
Odorless, colorless
Used as generalanesthetic
treatnarcolepsy
Cause euphoria, amnesia
=liquidX,liquidecstasy,G,scoop,cherrymeth,soap,saltywater,
����,��� ��
VTA
NAc
GABA
neuron
GABA
neuron
DA
neuron
GHB
GABAB
DA
GABA
receptor
GHB Addiction
Reward
Disinhibition
Gi/o
NAc
VTA
DA
Reward
GPCR
Hallucinogens
Includes LSD,mescaline,andpsilocybin
Psychosis-likemanifestations:
depersonalization,hallucinations,distorted
timeperception
Somaticsymptoms:dizziness,nausea,
paresthesias,andblurredvision
Tachyphylaxis=rapidtolerance
Not addictive, no dependence
(failtostimulatedopaminerelease)
Binds to 5HT2Areceptor
� increaseglutamatereleaseinthecortex
HallucinogensGPCR
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
DA
GABAreceptor
GluR
GPCR
Opioids
Cannabinoids
GHB
GPCRClassificationofDrugsofAbuse
Based on their moleculartarget
Ion channel
Nicotine
Hypnotics:Benzodiazepines&Barbiturates
Ketamine&PCP
Inhalants
Ion
channel
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
Nicotine Addiction
α4β2
nAChR
α4β2
nAChR
α7 nAChR
DA
Ca2+
GABAreceptor
GluR
Directly
é DA release
DA
Reward
Ion
channel
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
Nicotine Addiction
α4β2
nAChR
α4β2
nAChR
α7 nAChR
DA
Ca2+
GABAreceptor
GluR
Directly
é DA release
Indirectly
é DA release
DA
Reward
Ion
channel
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
Nicotine Addiction
α4β2
nAChR
α4β2
nAChR
α7 nAChR
DA
Ca2+
GABAreceptor
GluR
Directly
é DA release
Indirectly
é DA release
Desensitize DA
Reward
Ion
channel
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
Nicotine Addiction
α4β2
nAChR
α4β2
nAChR
α7 nAChR
DA
Ca2+
GABAreceptor
GluR
Directly
é DA release
Indirectly
é DA release
Desensitize DA
Reward
Nicotine Addiction
resting
Ion
channel
α4β2
nAChR
Nicotine Addiction
resting open
� DA releases
Ion
channel
α4β2
nAChR
Nicotine Addiction
resting open
� DA releases
desensitized
Initiation of craving
Ion
channel
α4β2
nAChR
Nicotine Addiction
resting open
� DA releases
desensitized chronic
desensitized
upregulated
enhancedcraving
drug-seekingbehavior
impulsivechoices
rewardsensitivity
Ion
channel
α4β2
nAChR
Treatment of Cigarette Addiction
Dose
Response
Full agonist
Partial agonist
Antagonist
channelfrequentlyopen
Ion
channel Treatment of Cigarette Addiction
Nicotine
(chewed,inhaled,or
transdermally)
nAchR agonist
ê Craving of cigarettes
Cytisine
Partial α4β2nAchR agonist
Varenicline
Dose
Response
Full agonist
Partial agonist
Antagonist
channelfrequentlyopen
Ion
channel
Treatment of Cigarette Addiction
Nicotine
(chewed,inhaled,or
transdermally)
nAchR agonist
ê Craving of cigarettes
Cytisine
Partial α4β2nAchR agonist
Varenicline
Dose
Response
Full agonist
Partial agonist
Antagonist
channelfrequentlyopen
stabilizeschannelinless
frequentlyopenstate,
notdesensitized
Ion
channel Treatment of Cigarette Addiction
Nicotine
(chewed,inhaled,or
transdermally)
nAchR agonist
ê Craving of cigarettes
Cytisine
Partial α4β2nAchR agonist
Varenicline
Dose
Response
Full agonist
Partial agonist
Antagonist
channelfrequentlyopen
stabilizeschannelinless
frequentlyopenstate,
notdesensitized
stabilizeschannelinclosed
state,notdesensitized
Ion
channel
Ketamine & PCP
Ion
channel
� noncompetitiveNMDAreceptor antagonist
PCP
= angeldust
Clubdrugs
Ketamine
� intenseanalgesia,amnesia,delirium,stimulant/depressantactions,
staggeringgait,slurredspeech,nystagmus
�High dose: catatonia,hallucinations,delusions,paranoia,lackofjudgment.
�Overdose: coma,extremelyhightemperature,seizures,rhabdomyolysis
Generalanesthetics
Clubdrugs
Inducesulcerativecystitis,vesicopathy
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
DA
GABAreceptor
GluR
Ion Channel
Nicotine
Ion
channel
ClassificationofDrugsofAbuse
Based on their moleculartarget
Amine
transporter
Cocaine
Amphetamine/methamphetamine
MDMA
Amine
transporter
Erythroxyloncoca
Blockthedopaminetransporter(DAT)� reward
Blockthenorepinephrinetransporter(NET)
� é pressure,tachycardia,ventriculararrhythmias
Cocaine
localanesthetic
dilatepupilsinophthalmologyhighlyaddictive
in CNS
in PNS Blockthevoltage-gatedsodiumchannels
� ê actionpotentials
Cocaine
NAc
VTA
DA
Reward
DAT
(dopaminetransporter)
Tyrosine
DOPA
Dopamine
TyrosineTH
DDC
cocaine
Cocaine Addiction
� blockstheuptakeofdopamine
Amine
transporter Amphetamine/methamphetamine
Amphetamine
Synthetic
Amine
transporter
Methamphetamine
� stimulant
Belongstothe‘β-phenylethylamines’
It’s chemicalstructures similarityto monoamine neurotransmitter
NAc
VTA
DA
Reward
DAT
Tyrosine
DOPA
Dopamine
TyrosineTH
DDC
Amphetamine Addiction
� block VMAT, reverse DAT
VMAT
VMAT
Amph
Amph
VMAT
(vesicularmonoaminetransporter)
DAT
Amine
transporter Clinical Uses of Amphetamine
Amine
transporter
� Reverse theactionofbiogenicaminetransporters
Target Effects Indications
NET
NEtransporter
éNE é arousal &ê sleep Narcolepsy
ADHD
(Attention-deficit/
hyperactivitydisorder)
DAT
DAtransporter
é DAeuphoria,
abnormalmovements
precipitatepsychoticepisodes
SERT
5-HTtransporter
é 5-HTHallucinogenic
Anorexigenic functions
Ecstasy, Adam, Dollar,
Fido,Bomb,���
MDMA (Methylene-dioxymethamphetamine)
Synthetic
MDMA
(Amphetamine-
relatedcompound)
SERT
(serotonin transporter)
5HT
MDMA
5HT
Amine
transporter
Hallucinogenic
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
DA
GABAreceptor
GluR
Transporter
Cocaine
Amphtamine
Amine
transporter
Addictive
Drugs
VTA NAc
GABA
neuronDA
neuron
Glu
neuron
Summary
DA
GABAreceptor
GluR
Transporter
Cocaine
Amphtamine
Ion Channel
Nicotine
GPCR
Opioids
Cannabinoids
GHB
Alcohol MetabolismMixed
Ethanol
CH3CH2OH
Acetaldehyde
CH3CHO
Acetate
CH3COO-
NAD+
NADH NADP+
NADPH + O2
NAD+
NADH
ADH MEOS
ALDH
ADH: Alcohol dehydrogenaseMEOS: Microsomal ethanol oxidizing systemALDH: Aldehyde dehydrogenase
Chronic alcohol
�éMEOS activity
Facialflushing
Lightheadedness
Palpitations
Nausea
HangoverALDHdeficient is
common in Asian
Alcohol
é GABA activity
ê Glutamate activity
é endogenousopioids
CNS depressant
� Addiction
Mixed
VTA NAc
GABA
NeuronDA
neuron DA
mGluR
MOR
NMDA
GABA
receptor
DA
endogenous
opioids
Effect of Alcohol
CNS Depressant
Loss of coordination,Poor judgment,Slow reflexes,Distorted vision,Loss of memory
é HR
Vasodilation
Vomit
Diuresis
Acute Effects
Mixed
Fatty liver, hepatitis,
Cirrhosis, liver cancer
Osteoporosis
Musclesweakness,
cramps,andatrophy
ê hormoneproduction,
stopmenstruating
Ulcers, gastritis
Chronic Effects
Tolerant to CNS Effect
Dependence
Effect of AlcoholMixed
� Teratogenic
Metal Retardation
Congenital Malformation
Congenital Heart Defects
Fetal Alcohol Syndrome
IntrauterineGrowthRestriction
Microcephaly
Poor Coordination
Minor Joint Anomalies
Underdevelopment of Midfacial Region
BloodAlcoholContent(BAC)
BAC
Life Threatening
• Loss of consciousness• Danger of life-threatening alcohol poisoning• Suppression of vital life function
Sever Impairment
• Speech, memory, coordination, attention, reaction time, balancesignificantly impaired
• Driving skill, judgment & decision-making dangerously impaired• Amnesia• Vomiting and other sign of alcohol poisoning• Loss of consciousness
Increased impairment
• Relaxation, intoxication• Speech, memory, attention, coordination, balance further impaired• Significant impairment in driving skills
Mild impairment
• Relaxation• Speech, memory, attention, coordination, balance impaired• Sleepiness
Mixed
0.05%
0.15%
0.30%
0.45%
Alcohol Withdrawal
Hyper-ExcitableresponseoftheCNS
é GABA activity
ê Glutamate activity
é endogenousopioids
CNS depressant
� Addiction
Minorwithdrawal Seizure Hallucinosis Delirium dremens
6-36 hr 6-48 hr 12-48 hr 48-96 hr
insomnia,tremulousness,mildanxiety,GIupset,headache,diaphoresis,palpitations,anorexia
generalizedtonic-clonic seizures
visual,auditory,ortactilehallucinations
Hallucinations,disorientation,tachycardia,hypertension,low-gradefever,agitation,diaphoresis
Alcohol Withdrawal symptoms:
Mixed Treatment of Alcohol Addiction
Ethanol
Acetaldehyde
Acetate
NAD+
NADHNADP
+
NADPH + O2
NAD+
NADH
ADH MEOS
ALDH
Fomepizole
Disulfiram
Vit. B
Acamprosate� é GABA activity�ê withdrawal symptom
Naltrexone�mu-opioid antagonist� ê craving of alcohol
Disulfiram� ê alcohol relapse
Cause discomfort
Mixed