Neurobiology of Substance Dependence

By-

Dr.Sunil SutharUnder Guidance of-

Dr.Suresh Gupta

CLINICAL FEATURES OF SUBSTANCE DEPENDENCE

Core criteria

Tolerance

Withdrawal

Craving

Impaired control/Compulsive use/Relapse

Socio-occupational dysfunction

Persistent use despite psycho/physical harm

ADDICTION DEFINED NEUROBIOLOGICALLY

Maladaptive alterations

in

spontaneous behavior

&

the behavioral response to re-administration of the drug

due to

drug-induced changes in the CNS (transmitters, receptors, circuits, volume)

Risk factor for substance abuse/dependence

Environmental• Availability of drugs• Poverty• Social change• Peer culture• Occupation• Cultural norms, attitudes• Policies on drugs:

tobacco and alcohol

Individual• Genetic disposition• Victim of child abuse• Personality disorders• Family disruption and

dependence problems• Poor performance at

school• Social deprivation• Depression and suicide

World Health Organization2004

Protective factor for substance abuse/dependence

Environmental• Economic situation• Situational control• Social support• Social integration• Positive life events

Individual• Good coping skills• Self-efficacy• Risk perception• Optimism• Health-related behaviour• Ability to resist social

pressure• General health behaviour

World Health Organization 2004

To understand neurobiology……..

• Neuroanatomy of reward system

• Evidence from animal studies

• Drugs of abuse: action & withdrawal

• Genetic predisposition

Natural rewards• Food, water, sex, &

nurturing are natural rewards.

• They allow organism to feel pleasure when eating, drinking, sex & being nurtured.

• They reinforce the behavior for repetition.

• These are required for survival.

• Brain has pathway responsible for reward.

The reward pathway Ventral Tegmental Area(VTA), Nucleus accumbens (NA) & Prefrontal cortex (PFC). VTA is connected to both NA &

PFC via this pathway sending information via its dopaminergic neurons,

Dopamine released in NA & PFC

• 3 brain areas mediate adaptive behaviour

Nucleus accumbens mediates reward related activities (positive valence);

Amygdala involved in fear motivated behaviour (negative valence)

Prefrontal cortex involved in decision making & predicting rewarding behaviour by:

- salience attribuition of environmental stimuli & - directing intensity of behavioural response.

• A balanced combination of motivational & affective states with external stimuli predicts reward, & determines overall output of a given behavioural response in acquiring natural reward

Dopamine•Receptors: D1, D2•Function: pleasure, euphoria, mood, motor function

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

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

Opioid peptides (Endorphins, Enkephalins)

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

The following neurotransmitters act on the reward pathway:

In all rewards, dopamine is the final activation chemical.

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

Serotonin Pathways: Mood, Memory, Sleep, Cognition

Raphe

Prefrontal cortex

Nucleusaccumbens

Ventraltegmentalarea

Dopamine

Ventral tegmental area, nucleus accumbens

Opioid Peptides

Nucleus accumbens, amygdala, ventral tegmental area

GABA

Amygdala, bed nucleusof stria terminalis

Glutamate

Nucleus accumbens

Neurotransmitters and anatomical sites involved in the acute reinforcing effects of drugs of abuse

Activation of reward pathway by an electrical stimulus: animal model

• Rats trained to press lever for electrical jolt to certain part of brain, ie NA

• Rats keep pressing lever to receive electric stimulus because it is pleasurable.

• Reward feeling is positive reinforcement, which occurs due to increased dopamine release.

• If dopamine release is prevented rat won't press for electrical jolt.

`Rewarding input to the

nucleus accumbens is due to bursts of dopamine release and thus phasic dopamine firing with "fun" and potentiation of conditioned reward as the result.

Connections of the amygdala with the nucleus accumbens communicate that emotions have been triggered by internal or external cues and signal an impulsive, almost reflexive response to be taken.

Substance abuse can arise from impairment of top-down inhibitory

control (impairement of prefrontal cortex)

behaviors implementation

The amygdala can not only learn that a drug causes pleasure but can also associate cues for that drug with pleasure. Thus, when cues are encountered, the amygdala signals dopamine neurons in the ventral tegmental area (VTA) that something good is coming; it may even signal the relief from drug craving (1 and 2). This leads to dopamine release in the nucleus accumbens (3), which triggers GABA-ergic neuron .

HYPOTHESIS

Dopamine is the basis of the ‘rewarding’ drug experience

Enhanced dopamine release in the meso-cortico-limbic circuit results in maladaptive drug-related behaviors

LACUNAE

Several drugs of abuse do not have prominent dopaminergic actions.

Role of NTs like GABA, glutamate and limbic and cortical brain areas unexplained.

Non-dopamine substrates can elicit addiction behaviors (Giro et al, 1996; Rocha et al, 1998).

Development of addiction may consist in part of a transition from dopamine-dependent behaviors to glutamate-dependent behaviors (as is true for natural rewards).

Cortical and allocortical areas prominent in ‘learning’ addiction behaviors.

Drug action in brain Acute drug administration modifies brain function,

Repeated exposure causes pervasive changes in brain function & persist long after individual stops taking drug.

Effects of chronic drug administration have been identified at cellular, molecular, structural & functional level.

An addicted brain is different from a non-addicted brain.

There are changes in brain metabolic activity, receptor availability, gene expression & responsiveness to environmental cues.

Name NT Circuit/Area

Mechanism

Amphetamine DA VTA and NA; brain stem

Displaces DA, NE from storage sites

Alcohol GABA, glutamate, DA, 5-HT, endorphins

Dose dependent:VTA;Cortical, limbic, basal ganglia, brain stem

Enhances GABAergic, inhibits glutamatergic actions

Cocaine DA, 5-HT, NE, glutamate

VTA; cortex, limbic area

Re-uptake inhibitor

Name NT Area/ circuit Mechanism

Nicotine DA, glutamate, GABA

VTA Direct receptor action

Cannabis Ach, DA, GABA, histamine, serotonin, NE, endorphins, PGs

Basal ganglia, cerebellum, hippocampus, dentate gyrus, cortex, brain stem

Enhance formation of DA, NE, 5-HT, GABA

Name NT Area/ Circuit

Mechanism

Phencyclidine Glutamate Hippocampus,anterior forebrain

NMDA receptor antagonist

Opioids Opioid receptors

Widespread: CNS, ANS

G-protein mechanisms: cAMP dependent kinases

Molecular Biology of Addiction: Addiction is a form of drug-induced neural plasticity

Upregulation of cAMP pathway• Occurs in response to chronic administration of drugs• Resulting activation of transcription factor

CREB(cAMP response element-binding)• Both mediate aspects of tolerance and dependency

Induction of another transcription factor, d FosB -• May contribute to sensitized responses to drug

exposure

Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

Basis for Plasticity: Summary

Drugs enter the brain and bind to an initial protein target

Binding perturbs synaptic transmission which in turn cause the acute behavioral effects of the drug

Acute effects of the drug do not explain addiction by themselves

Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

Addiction produces a change in brain structure and function (adaptation to the drug)

molecular and cellular changes in particular neurons alter functional neural circuits

This leads to changes in behavior consistent with addicted states

Addiction is therefore a form of drug induced neural plasticityRef: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001

Addiction process behaviour

Two factors modulate behaviour in addiction

(1) Reinforcement: stimulus increases the probability of response. positive reinforcement for pleasure from drug. negative reinforcement to relieve withdrawal symptoms – self-medication.

(2) Neuro-adaptation: Initial drug responses are attenuated or enhanced by repeated drug exposure

Withdrawal

Result of an abrupt cessation of the drug.

This syndrome involves:• disturbance of the autonomic nervous system• activation of the thalamus• release of corticotrophin releasing factor (CRF)• activation of the locus coeruleus (LC)

Withdrawal: Corticotrophin Releasing Factor (CRF) Involvement

The CRF system mediates the affective and somatic symptoms of drug withdrawal

Heart rateBlood pressureBlood glucose

Koob, 2008, PNAS 105(26), 8809-10, Copyright 2008, National Academy of Sciences, U.S.A. Response to stressors

Withdrawal: Neurotransmitter Involvement

Withdrawal Dopamine: dysphoria Dynorphin: dysphoria

Serotonin: dysphoria CRF: stress

Opioid Peptides: increased pain

GABA: anxiety, panic attacks NE: stress

Glutamate: hyperexcitability

Patient feels dysphoric, irritable, depressed and angry

“Drug craving” behavior: Type one

Cue triggered: animal develops conditioned self-stimulation in association with sensory stimuli or preferred place

If removed from environment for extended time And reintroduced to sensory stimuli or preferred place,

quickly reinstates behavior despite lack of reward Originates in hippocampus & amygdala; “emotional

memories” Neurotransmitter: glutamate

“Drug craving” behavior: Type two

Stress triggered: animal develops conditioned self-stimulatory behavior

Reward stopped & behavior extinguishes Relatively minor stress reinstates behavior & place

preference even in absence of further reward Mediated by corticotropin releasing factor in amygdala, &

NE from brainstem

Relapse studies

Stress induced relapse

‘Non-specific’

Pathways

• Mesolimbic dopamine system

• Corticotropin releasing factor (CRF): activates HPA axis – peripheral glucocorticoid release increased – facilitates excitatory input to VTA DA neurons

DRUG USE(Self-Medication)DRUG USE

(Self-Medication)

STRESSSTRESS

CRFCRF

AnxietyAnxiety

CRFCRF

AnxietyAnxiety

What Role Does Stress Play In Initiating Drug Use?

What Role Does Stress Play In Initiating Drug Use?

ProlongedDRUGUSE

ProlongedDRUGUSE

AbstinenceAbstinence

RELAPSERELAPSE

CRFCRF

AnxietyAnxiety

What Happens When A Person Stops Taking A Drug?

What Happens When A Person Stops Taking A Drug?

Cue-induced relapseEnvironmental stimuli – Pavlovian conditioning

Pathways

• Mesolimbic dopamine system: activation

• Amygdala

conditioning processes for stimuli

Cue-evoked recall

Activates VTA DA neurons (glutamatergic pathway) – increased DA in NAc

• Hippocampus, anterior cingulate cortex

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

• Variants of genes associated with drug abuse:

– FAAH missense mutation is associated with drug dependence.

– Polymorphism in promoter region of prodynorphin gene may beassociated with protection against cocaine dependence .

– Gene variants in nicotinic alpha 7 promoter associated with decreased expression of nicotinic alpha 7 subunit message in different regions of schizophrenic brains and with sensory gating defects in schizophrenics.

– 5HT1B receptor variant is associated with conduct disorder and Alcoholism.

Genes Implicated in Addiction

Genes Affecting Drug metabolism

• Ethanol - Acetaldehyde - Acetate-Individuals with defects in this metabolism pathway have a 5-10-fold reduction in risk for alcoholism

• Nicotine - Cotinine- Individuals with defects in this metabolism pathway appear to smoke fewer cigarettes

ADH2ADH3

ALDH2ALDH3

CYP2A6

Comorbidity of substance dependence and mental illness

Several hypotheses as to why mental illness and

substance dependence may co-occur:

1. There may be a similar neurobiological basis to both;

2. Substance use may help to alleviate some of the symptoms of the mental illness or the side effects of medication;

3. Substance use may precipitate mental illnesses or lead to biological changes that have common elements with mental illnesses.

Relationship of Addiction Behaviour and Treatment

Addictive component

Behavioural construct

Treatment focus

Pleasure Positive reinforcement

Motivational

Self-medication Negative reinforcement

AA and Motivational

Habit Conditioned positive reinforcement

Cognitive/behavioural

Habit Conditioned negative reinforcement

Cognitive/behavioural

(koob and nestler,1997)

TO SUMMARISE

Neuroplastic changes produced in various nuclei by repeated drug action integrated with environmental stimuli form behaviors characteristic of addiction

Corticofugal glutamate projection is necessary for the initiation of drug seeking

Different modes of stimuli inducing drug seeking involve distinct components of the circuit

All modalities of drug-seeking stimuli require dopamine transmission

Pharmacology Learning

Neuroplasticity

DRUG ENVIRONMENT

Motive circuit

Cortical and allocortical circuit

Molecular binding and cell signaling

SALIENCE AND SPECIFIC BEHAVIORAL RESPONSE

Neurobiological stages of addiction

Stage 1: Acute drug effects

Based on supraphysiological release of DA in the circuit

Induction of immediate early genes like c-fos (Graybiel et al, 1990)

Short-lived changes: hours to days

Stage 2: Transition to addictionAs a result of repeated drug use

Mediated by ΔFosB (Nye et al, 1995)

Reversible: diminish over days to weeks of

discontinuation

Stage 3: End-stage addictionLong-standing drug use

Enduring protein and cellular changes

Irreversible

Ref. books…..

• Stahls essential psychopharmacology 3rd edetion.• Kaplan and Sadocks comprehensive text book 9th edition. • Neuroscience of psychoactive substance use and

dependence.WHO,2004.