Drug abuse

By Mohie aldien elsayed (MD)

Learning Objectives• To be able to:• Identify the anatomical areas of the brain involved

in the reward pathway• Outline the neurotransmitter systems which

activate the reward pathway• Identify the anatomical areas and receptors

involved in activation from psychoactive drugs• Identify the anatomical areas and receptors

involved in the withdrawal from psychoactive drugs• Understand concepts relating to the development

of addiction

Nucleusaccumbens Ventral

tegmentalarea

Corpus Callosum Connects Hemispheres Creativity and Problem Solving

Cerebellum Coordinates muscles/ movement and thinking

processes

Hippocampus Forms Memories Coordinates thinking processes

Extended Amygdala

Emotional responses: fear and anger

Frontal Cortex Planning, Strategizing, Logic,

Judgment

Thalamus

Locuscoeruleus

Dopamine Pathways: Reward, Pleasure, Euphoria, Motor Function, Decision making

Serotonin Pathways: Mood, Memory, Sleep, Cognition

Raphe

Prefrontal cortex

Hippocampus

Nucleusaccumbens

Ventraltegmentalarea

Reward Pathway

Dopamine (Ventral tegmental area, nucleus accumbens)•Receptors: D1, D2•Function: pleasure, euphoria, mood, motor function

Serotonin •Receptors: 5HT3•Function: mood, impulsivity, anxiety, sleep, cognition

Cannabinoids•Receptors: CB1, CB2•Function: Pain, appetite, memory

Opioid peptides (Endorphins, Enkephalins) - Nucleus accumbens, amygdala, ventral tegmental area)

•Receptors: Kappa, Mu, Delta•Function: pain

In all rewards, dopamine is the final activation chemical

GABA (Amygdala, bed nucleusof stria terminalis)

Glutamate (Nucleus accumbens)

• There is a axonal network in the brain labeled the ‘reward pathway’• This reward pathway is activated by: - Food, water and sex, activities (such as sky diving, paragliding etc) and exercise -This reward pathway is also activated by drugs and alcohol

Drug Action & Reward Pathway

Alcohol•Binds/Inhibit GABAA: Dopaminergic activity is eventually increased in the VTA by inhibiting GABAergic interneurons•Also binds to NMDA, endorphins, activates secondary messages and has direct serotonergic effects

Heroin (Opioid)Binds to opioid receptors that inhibit GABAergic neurons that project to dopaminergic neurons in the VTA

CocaineBlocks the function of DAT (by binding

to the DAT and slowing transport)

NicotineActivates cholinergic neurons that project to dopaminergic neurons of the VTA

Methadone and levo-alpha-acetylmethadol (LAAM). Naltrexone

Naltrexone

nicotine replacement product (such as patches or gum) or an oral medication (such as bupropion)

Intoxication & Withdrawal: Neurotransmitter Involvement

Intoxication Dopamine: euphoria Opioid Peptides: analgesia, relaxation Serotonin: elevated mood GABA: decreased anxiety, less panic, relaxation

Withdrawal

Dopamine: dysphoria Serotonin: dysphoria Opioid Peptides: increased pain GABA: anxiety, panic attacks NPY: stress

Dynorphin: dysphoria CRF: stress Norepinephrine: stress Glutamate: hyperexcitability

Heart rateBlood pressureBlood glucose

Response to stressors

Stress:

GABAGABA + Alcohol

GABA + Alcohol

No AlcoholAcute

IntoxicationChronic

IntoxicationAdapted from Koob & Moal, 2006, reprinted with permission

The Development of Addiction• The use of the drug of abuse is increased to maintain euphoria or to avoid

dysphoria or withdrawal• The number of receptors gradually increases to counter for the continual

presence of the drug of abuse• The amount of neurotransmitter gradually decreases through depletion and

feedback inhibition• The reinforcing properties of the drug are thus gradually decreased (tolerance)• The need for drug to maintain this new homeostasis is therefore increased

(dependence begins)

*The resulting behaviours activate the reward pathway and a relationship is developed and becomes dominant.

*Behavioural repertoire is narrowed and eventually other important behaviors are ignored (e.g. familial, financial)•The reward and cognitive (decision making systems) are compromised resulting in an imbalance in impusive behaviours (e.g. violence, crime)

PFC AmygdalaNAc

The Development of Addiction: Long Term Changes

There is evidence of prolonged drug abuse resulting in both structural and functional brain changes

Decreases in CREB transcription factor in NAc (and extended

amygdala)

Decreases in metabolism in Orbito Frontal Cortex (OFC)

Decreases in dopamine D2 receptor binding (see figure below)

Volkow et al. Synapse 14 (2), 1993, pp. 169-177. © 1993 Synapse. Reprinted with permission of John Wiley & Sons, Inc.

The Development of Addiction: Long Term Changes

Dopamine transporter (DAT) binding followingheavy methamphetamine (METH) use

Control METH user

Volkow et al. Am. J. Psychiatry 158(3), pp. 377-382, 2001Reprinted with permission from the American Journal of Psychiatry (Copyright 2001). American Psychiatric Association.

The Development of Addiction: Genetics

Inheritability has been found to range from 40-60%Some variability between: gender and substances

Specifically:

4-fold increased risk in 1st degree relatives

4-fold increased risk also in adopted away children

The Development of Addiction: Genetics

Polymorphism is an altered basepair sequence (altered mRNA = altered protein = altered function)

Polymorphisms may - alter synthesis of dopamine- alter neurotransmitter releasewhich may diminish function of prefrontal cortex and exaggerate amygdala

Functional consequences relating to addiction include altered: initial response to intoxication, tolerance development, withdrawal effects, psychiatric comorbidity

AbstinenceAbstinence

Functionality inFamily, Work,

and Community

Functionality inFamily, Work,

and Community

Goals of Drug Treatment:Keeping an Eye on the Target

Reduced Criminal Behavior

Drug Abuse Treatment Core Components and Comprehensive

ServicesMedical

Mental Health

Vocational

Educational

LegalAIDS /

HIV Risks

Financial

Housing & Transportation

Child Care

Family

Continuing Care

Case Management

Urine Monitoring

Self-Help(AA/NA)

Pharmaco-therapy

Group/Individual Counseling

AbstinenceBasedIntake

Assessment

Treatment Plans

CoreTreatment

Etheridge, Hubbard, Anderson, Craddock, & Flynn, 1997 (PAB)

When to Consider Pharmacotherapy

Assess Pt For:• Severity of Concomitant Medical Illness: Patient’s ability to

tolerate medication?• Pregnancy: opioid therapy should be offered to pregnant

opioid/heroin addicts; medications that can be associated with adverse physical effects should be avoided (e.g.: disulfiram (Antabuse)

• Phase of Recovery: Medications for medical withdrawal or medication to assist with maintenance of abstinence following withdrawal

Phases of Substance Use that are Targets for Pharmacotherapy

• intoxication/overdose

• withdrawal/detoxification

• abstinence initiation/use reduction

• relapse prevention

• sequelae (psychosis, agitation, etc.)

Substances for which Pharmacotherapy

is Available

• Opioids

• Alcohol

• Benzodiazepines

• Tobacco (nicotine dependence)

• Cocaine

• Methamphetamine

• Hallucinogens

• Cannabis

• Solvents/Inhalants

Substances for which Pharmacotherapyis Not Available

PHARMACOTHERAPIES Opioid Addiction

› Methadone› Buprenorphine› Naltrexone

Tobacco Addiction› Nicotine Replacement

Therapy (NRT) Electronic Cigarettes, gum,

patches

› Bupropion (Zyban®)› Varenicline (Chantix®)

Lori L. Phelps California Association for Alcohol/Drug Educators, 2013

Alcohol Addiction› Naltrexone› Acamprosate (Campral®)

› Disulfiram (Antabuse®)› Topiramate (Topamax®)

Similarities & Differences AlcoholIntended effectAlcohol- CNSDepressant/relaxation, loss of inhibition

IntoxicationSlurred speech; loss of coordination;ataxia; decreased coordination, attention/concen-tration, memoryjudgment

W/d – detox4-12n hrs. p last drink Course hand tremor, sweating

Relapse Prevention*Disulfiram *Naltrexone (oral and injectable)-mu blocker*Acamprosate (↓glutamate release )*to help sleep Consider low dose trazodone (e.g. 25 mg) or qHS sedating antiDepressant (especially if pt has co-morbid depression,

e.g.:mirtazepine).

Sedatives /Hypnotics Anxiolytics

Induced effectBenzodiazapines& BarbituatesUse: to produceDrowsiness, anxiety

Intox-Benzo’s rarely fatal when taken alone; sx’s =Lethergy,Confusion;Barb’s –fatal in OD-coma,resp –cardiac arrest

W/d –detoxAtivan-10 hrs W/d sx’s-6-8 hrs p last doseValium –w/d up to 1 wkW/d= v/sNeed to taper off drug

Stimulants amphetamines/cocaine

Intended effectExcite – CNSLimited clinical use – high abuse potential Cocaine-highly addictive

Intox-High-euphoric feeling;hyper-activity/vigilanceTalkativeness, grandiosity,hallucinations, anxietyRepetitive behaviors, anger , fighting

W/d – detoxOccurs-few hrs- daysC/b marked dysphoria;fatigue; vivid & unpleasant dreams; hyper or insomnia; psychomotor act.

Opioids: morphine, heroin, meperidine, codeine, hydromorphone,

Induced effectPopular for abuse – desensitize user to both physio/psych pain-induce euphoria, well-being

Intox – develops quickly c/b apathy, lethergy,listlessness,judgment, psycho-motor retardation or agiation, constricted pupils,slurred speech Severe o d coma,Resp. arrest/death

W/d detox: Drug intake ceases or markedly; c/b Anxiety /restless., aching back ,legs, craving for opioidsHeroin –w/d 6-24hr;peak 2-3 days; Ends=5-7 days•Long acting mu agonist (Methadone ;Buprenorphine )•Naltrexone

Hallucinogens

Intended effectDistort users perception of reality

Intoxification/ODIntox= (Psychologic) anxiety,depression,Paranoid delusions, hallucinations (Physio) B/P,T,Pdilated pupils,sweating, blurred vision,tremors,decreased coordination

Withdrawal/DetoxNo withdrawal symptoms known-may crave drugProduce flashbacksMay continue up to 5 years after use.

Drug Action: Directe.g. Cocaine

•The mechanism of action for cocaine is via reuptake inhibition of dopamine•Dopamine release is promoted via the protein responsible for the reuptake of dopamine (dopamine transporter; DAT)Cocaine binds DAT = extracellular dopamine

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