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Drugs of Abuse Jen-Hsin Kao Ph.D. Drug of Abuse Abuse Addiction Drug of Abuse Abuse Addiction Drugs used in ways that are not medically approved Drug of Abuse Abuse Addiction a chronic, relapsing brain disease that causes compulsive drug seeking and use

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Page 1: DrugofAbuse Drugs of Abuse Abuse Addictionlms.ndmctsgh.edu.tw/sysdata/12/9212/doc/54a0c818d0634a61/...Drugs of Abuse Jen-HsinKaoPh.D. DrugofAbuse Abuse Addiction DrugofAbuse Abuse

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

Page 2: DrugofAbuse Drugs of Abuse Abuse Addictionlms.ndmctsgh.edu.tw/sysdata/12/9212/doc/54a0c818d0634a61/...Drugs of Abuse Jen-HsinKaoPh.D. DrugofAbuse Abuse Addiction DrugofAbuse Abuse

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

Page 3: DrugofAbuse Drugs of Abuse Abuse Addictionlms.ndmctsgh.edu.tw/sysdata/12/9212/doc/54a0c818d0634a61/...Drugs of Abuse Jen-HsinKaoPh.D. DrugofAbuse Abuse Addiction DrugofAbuse Abuse

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

Page 4: DrugofAbuse Drugs of Abuse Abuse Addictionlms.ndmctsgh.edu.tw/sysdata/12/9212/doc/54a0c818d0634a61/...Drugs of Abuse Jen-HsinKaoPh.D. DrugofAbuse Abuse Addiction DrugofAbuse Abuse

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

Page 5: DrugofAbuse Drugs of Abuse Abuse Addictionlms.ndmctsgh.edu.tw/sysdata/12/9212/doc/54a0c818d0634a61/...Drugs of Abuse Jen-HsinKaoPh.D. DrugofAbuse Abuse Addiction DrugofAbuse Abuse

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

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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

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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

Page 8: DrugofAbuse Drugs of Abuse Abuse Addictionlms.ndmctsgh.edu.tw/sysdata/12/9212/doc/54a0c818d0634a61/...Drugs of Abuse Jen-HsinKaoPh.D. DrugofAbuse Abuse Addiction DrugofAbuse Abuse

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

Page 9: DrugofAbuse Drugs of Abuse Abuse Addictionlms.ndmctsgh.edu.tw/sysdata/12/9212/doc/54a0c818d0634a61/...Drugs of Abuse Jen-HsinKaoPh.D. DrugofAbuse Abuse Addiction DrugofAbuse Abuse

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

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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

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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

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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

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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