The Neuroscience of Drug Addiction and Therapy

V.Niklesh Rao

Under the guidance of K.Raj Kiran sir

Profile link: http://www.pharmainfo.net/nik

► Introduction► Key Definitions► Reward pathway responsible for

Addictive Changes► Stages of the Addiction Cycle► Neurochemical Changes Associated

with the Drug Use, Dependence and Relapse

► Therapy► Conclusion

Contents

Introduction• Alcohol

– 18 million Americans abuse or are dependent on Alcohol. • Smoking --In US, approximately 440,000 persons die per year of a cigarette smoking & attributable illness

• Opioid Dependency– Dependency has been growing rapidly:

• From 1990 to 2001, the number of people who used prescription painkillers recreationally for the first time grew by 335% to include almost 2.5 million people.

Estimated Prevalence Among 15-54 Year Olds ofNonmedical Use and Dependence Among Users

(1990-1992) (NCS)

Ever UsedPrevalence of Dependence

Dependence Among Users

Tobacco

Alcohol

Illicit Drugs

Cannabis

Cocaine

Drugs

75.6

91.5

51.0

46.3

16.2

24.1

14.1

7.5

4.2

2.7

31.9

15.4

14.7

9.1

16.7

Key Definitions

Drug Addiction — Chronically relapsing disorder that is characterized by a compulsion to seek and take drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug is prevented (here, defined as the “dark side” of addiction)

Nucleus Accumbens and Extended Amygdala — Forebrain structures involved in the rewarding effects of drugs of abuse. Composed of central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the nucleus accumbens

Reward pathway responsible for Addictive Changes

Reward pathway responsible for Addictive Changes

Neurochemical Circuitry in Drug Reward

Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens

Summary- Neurocircuitry of Addiction

• Reward Circuit- nucleus accumbens and extended amygdala (bed nucleus of the stria terminalis and central nucleus of the amygdala)

• “Craving” Circuit- dorsal prefrontal cortex, basolateral amygdala

• “Compulsivity” Circuit- ventral striatum, ventral pallidum,medial thalamic- orbitofrontal cortical loop

Stages of the Addiction Cycle

Stages of the Addiction Cycle

Neurobiological Substrates for the Acute Reinforcing Effects of Drugs of Abuse

Neurotransmitter

Dopamine

Opioid Peptides

GABA

Glutamate

Site

Ventral tegmental area, nucleus accumbens

Nucleus accumbens, amygdala, ventral tegmental area

Amygdala, bed nucleus of stria terminalis

Nucleus accumbens

Neurochemical Changes Associated with the Drug Use, Dependence and Relapse

Neurotransmitters Implicated in the Motivational Effects of Withdrawal from Drug of Abuse

Dopamine … “dysphoria”

Serotonin … “dysphoria”

GABA … anxiety, panic attacks

NPY … anti-stress

Dynorphin … “dysphoria”

CRF … stress

Norepinephrine … stress

Glutamate….hyperexcitability

Common Molecular Changes Associated with Dependence

• Dopamine D-2 receptor binding- decreased in human imaging studies in dependent subjects• CREB ( cyclic adenosine monophosphate response element binding protein) transcription factor-

decreased in nucleus accumbens and extended amygdala during the development of dependence

Reward Transmitters Implicated in the Positive Motivational Effects of Drugs of Abuse

Dopamine

Opioid peptides

GABA

Glutamate

Positive Hedonic Effects

Chronic Use: Hedonic Homeostatic Dysregulation

Hed

onic

Sca

le Normal Affective Responseto Drugs/Alcohol

Altered Dysregulated Set-Pointfollowing chronic drug use

Hedonic Set Point is Altered with Chronic Drug Use

Initially use toget high…

Now use to “get normal”

“Cravings”

“Feel good”

“Feel bad”

Animal Models for the Different Stages of the Addiction Cycle

• Animal Models for the Binge/Intoxication Stage1. Oral or intravenous drug self-administration2. Brain stimulation reward3. Place preference

• Animal models for the Withdrawal/Negative Affect Stage1. Brain stimulation reward2. Place aversion

• Animal Models for the Transition to Addiction1. Dependence-induced drug taking2. Escalation in drug self-administration with prolonged access 3. Drug taking despite aversive consequences

• Animal Models for the Preoccupation/Anticipation (“Craving”) Stage1. Drug- induced reinstatement2. Cue- induced reinstatement3. Alcohol Deprivation Effect4. Stress- induced reinstatement

Mood Changes Associated with Plasma Levels of Cocaine during Coca Paste Smoking

Cocaine Self-Administration

Extracellular DA and 5-HT in the Nucleus Accumbens During Cocaine Self-Administration

and Withdrawal

CNS Actions of Corticotropin Releasing Factor (CRF)

Ethanol Dependence Induction

Extracellular CRF Levels in the CentralAmygdala During Ethanol Withdrawal

Effect of CRF Antagonist D-Phe-CRF12-41

– Central Nucleus of the Amygdala –

Craving-Type 1

• “Craving”- induced by stimuli that have been paired with ethanol self-administration such as environmental cues

• Termed conditioned positive reinforcement in experimental psychology

• An animal model of craving- type 1 is cue induced reinstatement where a cue previously paired with access to ethanol reinstates responding for a lever that has been extinguished.

Reinstatement

Neurobiological Effects of Exposure to Drug-Associated Contextual Stimuli

SA EXT S- S+Daily Sessions of Self-Administration

Common Molecular Changes Associated with Dependence

• Dopamine D-2 receptor binding- decreased in human imaging studies in dependent subjects

• CREB ( cyclic adenosine monophosphate response element binding protein) transcription factor- decreased in nucleus accumbens and extended amygdala during the development of dependence

• Delta-FosB transcription factor-changed during protracted abstinence to drugs of abuse

Key Common Neurocircuitry Elements in Drug Seeking Behavior of Addiction

Craving-Type 1• “Craving”- induced by stimuli that have been paired with ethanol self-administration such as

environmental cues• Termed conditioned positive reinforcement in experimental psychology

Craving-Type 2• State of protracted abstinence in alcoholics weeks after acute withdrawal• Conceptualized as a state change characterized by anxiety and dysphoria or a residual negative

affective state that combines with Craving-Type 1 situations to produce relapse to excessive drinking

Therapy• No single treatment is appropriate for all individualsNo single treatment is appropriate for all individuals• Effective treatment attends to multiple needs of the individual, not just his/her drug useEffective treatment attends to multiple needs of the individual, not just his/her drug use• Treatment must address medical, psychological, social, vocational, and legal problemsTreatment must address medical, psychological, social, vocational, and legal problems

Duration of TreatmentDuration of Treatment

• Depends on patient problems/needsDepends on patient problems/needs• Less than 90 days is of limited/no effectiveness for residential/outpatient settingLess than 90 days is of limited/no effectiveness for residential/outpatient setting• A minimum of 12 months is required for methadone maintenanceA minimum of 12 months is required for methadone maintenance• Longer treatment is often indicatedLonger treatment is often indicated

Medical DetoxificationMedical Detoxification

• Detoxification safely manages the physical symptoms of withdrawaDetoxification safely manages the physical symptoms of withdrawa• lOnly first stage of addiction treatmentlOnly first stage of addiction treatment• Alone, does little to change long-term drug useAlone, does little to change long-term drug use

Medications for Alcohol Dependence

• Disulfiram (Antabuse)- FDA approved 1954

• Naltrexone (ReVia)- FDA approved 1994

• Acamprosate- FDA approved 2004

Therapy

Counseling and Other Behavioral TherapiesCounseling and Other Behavioral Therapies

DrugResistanceSkills

Replace Drug UsingActivities

Motivation

Problem Solving Skills

Interpersonal Relationships

Conclusion• Drug abuse is an issue of global concern especially among the youth and adolescent population.Drug abuse is an issue of global concern especially among the youth and adolescent population.• Drug addiction is the major cause of behavioral disturbances and major cause of criminal Drug addiction is the major cause of behavioral disturbances and major cause of criminal

activity.activity.• The main objective of study of neuroscience of drug addiction is to effectively develop therapy The main objective of study of neuroscience of drug addiction is to effectively develop therapy

for the individuals to rid of their drug seeking behavior and to stabilize their behavior.for the individuals to rid of their drug seeking behavior and to stabilize their behavior.• Based on the studies, newer, more effective pharmacotherapeutic strategies may be developed.Based on the studies, newer, more effective pharmacotherapeutic strategies may be developed.

References • www.nida.nih.gov• www.drugabuse.gov• National Institute on Alcohol Abuse and Alcoholism• National Institute on Drug Abuse• California Society of Addiction Medicine• RANG & DALE'S PHARMACOLOGY • Basic and Clinical Pharmacology by Bertram G. Katzung• Goodman & Gilmann’s Pharmacological Basis of Therapeutics

Acknowledgement I am grateful to our college principal Dr.Y.Srinivasa Rao sir for providing an

opportunity to present this seminar and also all the staff members who have extended their help and valuable suggestions and have provided all the help they could, I would especially like to thank my guide K.Raj Kiran sir for thoroughly supporting me to prepare and present my presentation.

I would like to express my gratitude to pharmainfo.net for giving me an opportunity to present the powerpoint presentation on the chosen topic.

Thank You