1. Drug abuse By Mohie aldien elsayed (MD)

2. 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

3. Nucleus accumbens Ventral tegmental area 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 Locus coeruleus

4. Dopamine Pathways: Reward, Pleasure, Euphoria, Motor Function, Decision making Serotonin Pathways: Mood, Memory, Sleep, Cognition Raphe Prefrontal cortex Hippocampus Nucleus accumbens Ventral tegmental area

5. 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 nucleus of 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

6. Drug Action & Reward Pathway Alcohol Binds/ Inhibit GABA A : 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 Cocaine Blocks the function of DAT (by binding to the DAT and slowing transport) Nicotine Activates cholinergic neurons that project to dopaminergic neurons of the VTA Methadone and levo-alpha- acetylmethadol (LAAM). Naltrexone Naltrexone n icotine replacement product (such as patches or gum) or an oral medication (such as bupropion)

7. 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 rate Blood pressure Blood glucose Response to stressors Stress: GABA GABA + Alcohol GABA + Alcohol No Alcohol Acute Intoxication Chronic Intoxication Adapted from Koob & Moal, 2006, reprinted with permission

8. 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

9. 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.

10. The Development of Addiction: Long Term Changes Dopamine transporter (DAT) binding following heavy methamphetamine (METH) use ControlMETH user Volkow et al. Am. J. Psychiatry 158(3), pp. 377-382, 2001 Reprinted with permission from the American Journal of Psychiatry (Copyright 2001). American Psychiatric Association.

11. 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

12. The Development of Addiction: Genetics Polymorphism is an altered base pair sequence (altered mRNA = altered protein = altered function) Polymorphisms may - alter synthesis of dopamine - alter neurotransmitter release which 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

13. AbstinenceAbstinence Functionality in Family, Work, and Community Functionality in Family, Work, and Community Goals of Drug Treatment: Keeping an Eye on the Target Reduced Criminal Behavior

14. Drug Abuse Treatment Core Components and Comprehensive Services Medical Mental Health Vocational Educational Legal AIDS / HIV Risks Financial Housing & Transportation Child Care Family Continuing Care Case Management Urine Monitoring Self-Help (AA/NA) Pharmaco- therapy Group/Individual Counseling Abstinence Based Intake Assessment Treatment PlansCoreTreatment Etheridge, Hubbard, Anderson, Craddock, & Flynn, 1997 (PAB)

15. When to Consider Pharmacotherapy Assess Pt For: Severity of Concomitant Medical Illness: Patient’s ability to tolerate medication? 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) 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 Phase of Recovery: Medications for medical withdrawal or medication to assist with maintenance of abstinence following withdrawal

16. Phases of Substance Use that are Targets for Pharmacotherapy intoxication/overdose withdrawal/detoxification abstinence initiation/use reduction relapse prevention sequelae (psychosis, agitation, etc.)

17. Substances for which Pharmacotherapy is Available Opioids Alcohol Benzodiazepines Tobacco (nicotine dependence ) Cocaine Methamphetamine Hallucinogens Cannabis Solvents/Inhalants Substances for which Pharmacotherapy is Not Available

18. 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 ®)

19. Similarities & Differences Alcohol Intended effect Alcohol- CNS Depressant/ relaxation, loss of inhibition Intoxica tion Slurred speech; loss of coordinati on; ataxia; decreased coordinati on, attention/ concen- tration, memory judgment W/d – detox 4-12n 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 anti Depressant (especially if pt has co-morbid depression, e.g.:mirtazepine).

20. Sedatives /Hypnotics Anxiolytics Induced effect Benzodiazapi nes& Barbituates Use: to produce Drowsiness,  anxiety  anxietyIntox- Benzo’s rarely fatal when taken alone; sx’s = Lethergy,Confusion; Barb’s –fatal in OD-coma,resp – cardiac arrest W/d – detox Ativan-10 hrs W/d sx’s-6-8 hrs p last dose Valium –w/d up to 1 wk W/d=  v/s Need to taper off drug

21. Stimulants amphetamines/cocaine Intended effect Excite – CNS Limited clinical use – high abuse potential Cocaine-highly addictive Intox- High-euphoric feeling;hyper- activity/vigilance Talkativeness, grandiosity,hallucin ations, anxiety Repetitive behaviors, anger, fighting W/d – detox Occurs-few hrs- days C/b marked dysphoria; fatigue; vivid & unpleasant dreams; hyper or insomnia;  psychomotor act.

22. Opioids: Opioids: morphine, heroin, meperidine, codeine, hydromorphone, Induced effect Popular for abuse – desensitize user to both physio/psych pain-induce euphoria, well-being Intox – develops quickly c/b apathy, lethergy,listless ness,  judgment, psycho-motor retardation or agiation, constricted pupils,slurred speech Severe o d  coma, develops quickly c/b apathy, lethergy,listless ness,  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 opioids Heroin –w/d 6-24  hr; peak 2-3 days; Ends=5-7 days ( Long acting mu agonist (Methadone ;Buprenorphine ) Naltrexone

23. Hallucinogens Intended effect Distort users perception of reality Intoxification/OD Intox= (Psychologic) anxiety,depression, Paranoid delusions, hallucinations (Physio)  B/P,T,P dilated pupils,sweating, blurred vision,tremors, decreased coordination Withdrawal/Detox No withdrawal symptoms known -may crave drug Produce flashbacks May continue up to 5 years after use.

24. Drug Action: Direct e.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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