Neuroscience of Substance Abuse and Dependence

8/13/2019 Neuroscience of Substance Abuse and Dependence

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Neuroscience of Substance

Abuse and Dependence

Dr Shambu SugathanC/P: Dr Preethi Rebello


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Introduction

Drug addiction constitutes a chronicCNS disorder characterized by

recurrent episodes of relapse in which

individuals resume drug-seeking anddrug-taking behavior


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Detailed information exists on:

the neural pathways that underlie drug

reinforcement and drug-seeking

behavior,

selective alterations in neurochemical

activity

persisting neuroadaptations inneuronal signal transduction pathways


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Phases of the Addiction Process

Addiction has been generally definedas uncontrolled, compulsive use of a

substance over time.

An initial period of drug use occurs

without clear evidence of addictive

behavior, followed by ever increasinglevels of drug consumption that

eventually leads to addiction.


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Stages of the Addiction Cycle


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The process where addiction beginsinvolves complex changes in

mechanisms of positive reinforcement,

negative reinforcement, and hedonicdysregulation.

It also has been described in terms ofpersisting forms of maladaptive

learning and response patterns.


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Positive Reinforcement

definedas the process by which presentation

of a stimulus (drug) increases the

probability of a response (nondependent drug taking paradigms).


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Negative Reinforcement

defined asa process by which removal of anaversive stimulus (negative emotional

state of drug withdrawal) increases theprobability of a response.


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In individuals with substance usedisorders, periods of chronic

substance use are invariably followed

by periods of abstinence andwithdrawal, during which various

withdrawal signs at the behavioral and

biological levels become manifested.


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These withdrawal episodes have beenmodeled using both active extinction

of drug-seeking behavior as well as

forced abstinence from drugavailability and drug context.


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Periods of withdrawal from drug useare followed by instances of relapse,

which are reinitiated by various trigger

factors: internal (e.g., stress states)

external (e.g., previously drug-paired

environmental cues)


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Clinical evidence has clearlyestablished the ability of drug-

associated environmental cues to elicit

drug craving and consequentlyreinstate drug-seeking and drug-

taking.

Conditioned-cued responses have

been demonstrated for a variety of

drugs of abuse.


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Nucleus

accumbens Ventral

tegmental

area

Corpus Callosum

Connects Hemispheres

Creativity and Problem

Solving

Cerebellum

Coordinates muscles/ movement

and thinking processes

Hippocampus

Forms Memories

Coordinates thinkin rocesses

Extended Amygdala

Emotional responses: fear

and anger

Frontal Cortex

Planning, Strategizing, Logic,

Judgment

Thalamus

Locus

coeruleus


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Brain Pathways of Reward and

Addiction Pathways That Underlie Drug

Reinforcement:

The common neural substrate of all

addictive drugs, including alcohol, isthe mesocorticolimbic dopamine

pathway.


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

Serotonin Pathways: Mood, Memory, Sleep, Cognition

Raphe

Prefrontal cortex

Hippocampus

Nucleus

accumbensVentral

tegmentalarea


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Reward Pathway

Dopamine

Receptors: D1, D2

Function: pleasure,euphoria, mood, motorfunction

Serotonin

Receptors: 5HT3

Function: mood, impulsivity,anxiety, sleep, cognition

Cannabinoids

Receptors: CB1, CB2

Function: Pain, appetite,memory

Opioid peptides (Endorphins,Enkephalins)

Receptors: Kappa, Mu, DeltaFunction: pain

The following neurotransmitters act on the reward pathway:

In all rewards, dopamine is the final activation chemical


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Reward Pathway

Dopamine

Ventral tegmental area,nucleus accumbens

Opioid Peptides

Nucleus accumbens,

amygdala, ventral

tegmental area

GABA

Amygdala, bed nucleus

of stria terminalis

Glutamate

Nucleus accumbens

Neurotransmitters and anatomical sites involved in the acute

reinforcing effects of drugs of abuse


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Repeated exposure to nondrugrewards (e.g. food) activates this

pathway in a manner that does not

result in supranormativeneurotransmitter release and

stimulation of postsynaptic signaling.


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In contrast, drugs of abuse canhijack the reward system in a

manner that produces abnormal levels

of neuronal activation

Causes subsequently profound and

long-lasting adaptive changesfollowing repeated exposure to the

drug and intervening withdrawal

periods.


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Extensive data using a variety ofexperimental approaches have shown

that mesolimbic dopamine pathway

activity is required for the primaryreinforcing effects of drugs of abuse

Extracellular dopamine release in the

terminal fields of the nucleusaccumbens is significantly enhanced

during drug self-administration


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Primary reinforcement by drugs ofabuse engages a widespread network

of the brain's motivational pathways

including: cortical regions and limbic structures

such as the prefrontal cortex,

amygdala, hippocampus, andhypothalamus.


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Differences across classes of abuseddrugs have been recognized.

Psychostimulants such as cocaine andamphetamine directly increase levels ofdopamine and other monoamines.

Opioids opiate receptors in VTAdecrease the activity of inhibitory GABA

interneurons, subsequently resulting in agreater release of dopamine in forebrainregions


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Other drugs, including nicotine andcannabinoids, lead to enhanced

dopamine release through the

activation of their respective receptorsand subsequent disinhibition or

excitation of dopamine neurons.


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Conditioned Cue-Induced

Relapse Through a process of associative

learning, previously neutral stimuli

acquire incentive-motivational

properties during repeated pairingswith consumption of an abused drug.

These drug-associated stimuli

subsequently elicit subjective drugdesire and physiological arousal in a

manner that perpetuates a return to

further drug use


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In the animal model several lines ofresearch have extensively implicated

cortico-striato-limbic pathways in the

development and maintenance ofdrugcue associations that drive drug-

seeking behavior after periods of

withdrawal.


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Of particular interest has been theamygdala,.

Excitotoxic lesions of the basolateral

amygdala have no effect on cocaine-taking during daily cocaine self-

administration


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But these lesions completely abolishthe reinstatement of cocaine-seekingproduced by cocaine-paired cues longafter the cessation of cocaine self-administration

Other studies have examined drug-seeking after reversible forms of

neuronal inactivation of discrete brainregions with sodium channel blockersor GABA receptor agonists.


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Studies have demonstrated that theamygdalar mediation of conditioned-cued reinstatement is dopamine-dependent,

Intrabasolateral amygdala blockade ofD1receptors abolishes cue-induced

reinstatement, while enhancingdopamine levels in the amygdaladuring cue presentation will potentiatecocaine-seeking.


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Recent studies have implicated theamygdala in the acquisition and

consolidation of drugcue

associations.

Amygdalar disruption during the

memory reconsolidation of previouslylearned cues will abolish cue-induced

relapse.


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Other brain regions involved inconditioned-cued reinstatement

include discrete subregions of the

prefrontal cortex and striatum.

Pharmacological inactivation of the

dorsal medial PFC, lateral OFC, or thenucleus accumbens core subregion

significantly attenuates cue-induced

cocaine-seeking.


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Drug-induced adaptive changes in thecircuitry that drives stimulusresponse

(SR) learning, in particular the dorsal

regions of the striatum (caudate andputamen), which are known to

mediate habitual responses acquired

by the strengthening of SRassociations.


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It has been well-established thatpsychostimulant administration

produces the most notable changes in

gene expression in the dorsalstriatum, in contrast to the lesser

degree of changes observed in the

ventral striatum. Furthermore, the caudate-putamen

receives the densest innervation by

dopamine afferents.


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In rodent models, extracellulardopamine in the caudate-putamen is

increased during response for a

cocaine-associated cue, whileinactivation of the caudate-putamen

by pharmacological means blocks

response for cocaine-associated cuesor context.


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Recent studies PET in cocaine-dependent subjects during cue-

induced craving have shown that

dopamine in the caudate-putamen, butnot in the ventral striatum ie NA is

positively correlated with self-reports

of craving.


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In sum, a growing body of evidencesupports the idea of long-term

changes in striatal circuitry, whereby

the caudate-putamen criticallymediates habitual patterns of drug-

seeking at the time of relapse.


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Drug-Primed Reinstatement

Small doses of an abused drug caninitiate subjective states of drug desire

that prompt renewed drug consumption

in humans.

One notable contrast in the neural

circuitry underlying drug-primed versus

conditioned-cued reinstatement of

cocaine-seeking is the fact that

amygdala inactivation has no effect on

cocaine-primed reinstatement


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Prelimbic cortex, NA core, and ventralpallidum are also involved in drug

induced reinstatement

Neurotransmitter projections may

drive cocaine-primed reinstatement,

including dopaminergic inputs to theinfralimbic cortex and NA shell.


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Stress-Induced Reinstatement

Stress clearly plays a role inacquisition, maintenance, and relapse

with drugs of abuse.

Stress in rats (usually footshock

presented in the drug-paired context)

has been commonly used to studystress-induced reinstatement of drug-

seeking..


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Examination of the pathways thatmediate footshock-induced stress

have shown that some of the same

circuitry required for conditioned-cuedor drug-primed reinstatement of

cocaine-seeking is also necessary for

stress-induced reinstatement,

including the prelimbic cortex and

nucleus accumbens


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Inactivation of extended amygdalastructures, including the central

amygdala and bed nucleus of the stria

terminalis, will attenuate stress-induced reinstatement,

while basolateral amygdala

inactivation fails to block stress-induced reinstatement


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The withdrawal/negative affect stageconsists of key motivational elements

such as:

chronic irritability, emotional pain,malaise, dysphoria, alexithymia, and

loss of motivation for natural rewards,

characterized in animals by increasesin reward thresholds during withdrawal

from all major drugs of abuse.


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Significant plasticity occurs in theneurotransmitter circuits identified as

critical for the acute reinforcing effects

of drugs of abuse. In animal models of the transition to

addiction, increases in brain reward

threshold (decreased reward) occurthat temporally precede and highly

correlate with escalation in drug intake


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During acute withdrawal, there isdecreased activity of the reward

systems as well as decreased opioid

peptide, GABA, glutamate, andneuropeptide Y activity in elements of

the extended amygdala and/or

nucleus accumbens


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However, as dependence andwithdrawal develop, brain antireward

systems such as corticotropin-

releasing factor (CRF),norepinephrine, and dynorphin are

recruited


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For example, extracellular CRF in theextended amygdala is increased

during acute withdrawal from drugs of

abuse, and critically, CRF antagonistsblock excessive drug-taking during

dependence


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The observation that CRF receptorantagonists in the amygdala can block

excessive drug intake associated with

the development of dependenceprovides a compelling example of a

key aspect of the plasticity of the

extended amygdala in the

development of addiction.


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The development of the aversiveemotional state that drives the

negative reinforcement of addiction

may also contribute to the criticalproblem in drug addiction of chronic

relapse, where addicts return to

compulsive drug-taking long after

acute withdrawal


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This effect suggests that stress maysensitize an individual to be more

attentive to drug-paired cues, increase

the incentive salience of the cues, orperhaps increase motivation to reduce

negative affect states through

renewed drug use.


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CONCLUSION

Maladaptive alterations in spontaneousbehavior & the behavioral response tore-administration of the drug due todrug-induced changes in the CNS(transmitters, receptors, circuits,volume)


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The classic anatomical areas of thebrain involved in the reward pathway

include the nucleus accumbens,

ventral tegmental area and theprefrontal cortex

Dopaminergic activity is the finalchemical action in most behaviours

relating to reward


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Drugs of abuse may work withreceptors and transporters to directly

or indirectly influence dopaminergic

activity

Addiction is the result of and results in

lasting changes to neurocircuitry,cellular and molecular mechanisms.

Neuroscience of Substance Abuse and Dependence

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