Neuroscience of Substance Abuse and Dependence

Dr Shambu Sugathan C/P: Dr Preethi Rebello

Introduction

Drug addiction constitutes a chronic CNS disorder characterized by recurrent episodes of relapse in which individuals resume drug-seeking and drug-taking behavior

Detailed information exists on: the neural pathways that underlie drug reinforcement and drug-seeking behavior, selective alterations in neurochemical activity persisting neuroadaptations in neuronal signal transduction pathways

Phases of the Addiction Process

Addiction has been generally defined as uncontrolled, compulsive use of a substance over time.

An initial period of drug use occurs without clear evidence of addictive behavior, followed by ever increasing levels of drug consumption that eventually leads to addiction.

Stages of the Addiction Cycle

The process where addiction begins involves complex changes in mechanisms of positive reinforcement, negative reinforcement, and hedonic dysregulation. It also has been described in terms of persisting forms of maladaptive learning and response patterns.

Positive Reinforcement defined as the process by which presentation of a stimulus (drug) increases the probability of a response (non dependent drug taking paradigms).

Negative Reinforcement defined as a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal) increases the probability of a response.

In individuals with substance use disorders, periods of chronic substance use are invariably followed by periods of abstinence and withdrawal, during which various withdrawal signs at the behavioral and biological levels become manifested.

These withdrawal episodes have been modeled using both active extinction of drug-seeking behavior as well as forced abstinence from drug availability and drug context.

Periods of withdrawal from drug use are 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)

Clinical evidence has clearly established the ability of drugassociated environmental cues to elicit drug craving and consequently reinstate drug-seeking and drugtaking.

Conditioned-cued responses have been demonstrated for a variety of drugs of abuse.

Frontal Cortex

Corpus Callosum
Connects Hemispheres Creativity and Problem Solving

Planning, Strategizing, Logic, Judgment

Cerebellum Coordinates muscles/ movement and thinking processes

Thalamus

Nucleus accumbens
Extended Amygdala

Ventral tegmental area

Locus coeruleus
Hippocampus

Emotional responses: fear and anger

Forms Memories Coordinates thinking processes

Brain Pathways of Reward and Addiction

Pathways That Underlie Drug Reinforcement: The common neural substrate of all addictive drugs, including alcohol, is the mesocorticolimbic dopamine pathway.

Reward Pathway
There is a axonal network in the brain labeled the reward pathway This reward pathway is activated by: Food, water and sex, activities and exercise also activated by drugs

Dopamine Pathways: Reward, Pleasure, Euphoria,

Motor Function, Decision making

Prefrontal cortex Hippocampus Nucleus accumbens

Ventral tegmental area

Raphe Serotonin Pathways: Mood, Memory, Sleep, Cognition

Reward Pathway
The following neurotransmitters act on the reward pathway:
Dopamine
Receptors:

Serotonin
Receptors:

D1, D2 Function: pleasure, euphoria, mood, motor function

5HT3 Function: mood, impulsivity, anxiety, sleep, cognition

Cannabinoids
Receptors:

CB1, CB2 Function: Pain, appetite, memory

Opioid peptides (Endorphins, Enkephalins)

Receptors:

Kappa, Mu, Delta Function: pain

In all rewards, dopamine is the final activation chemical

Reward Pathway
Neurotransmitters and anatomical sites involved in the acute reinforcing effects of drugs of abuse
Dopamine
Ventral tegmental area, nucleus accumbens GABA Amygdala, bed nucleus of stria terminalis

Opioid Peptides
Nucleus accumbens, amygdala, ventral tegmental area Glutamate Nucleus accumbens

Repeated exposure to nondrug rewards (e.g. food) activates this pathway in a manner that does not result in supranormative neurotransmitter release and stimulation of postsynaptic signaling.

In contrast, drugs of abuse can hijack the reward system in a manner that produces abnormal levels of neuronal activation Causes subsequently profound and long-lasting adaptive changes following repeated exposure to the drug and intervening withdrawal periods.

Extensive data using a variety of experimental approaches have shown that mesolimbic dopamine pathway activity is required for the primary reinforcing effects of drugs of abuse Extracellular dopamine release in the terminal fields of the nucleus accumbens is significantly enhanced during drug self-administration

Primary reinforcement by drugs of abuse engages a widespread network of the brain's motivational pathways including: cortical regions and limbic structures such as the prefrontal cortex, amygdala, hippocampus, and hypothalamus.

Differences across classes of abused drugs have been recognized. Psychostimulants such as cocaine and amphetamine directly increase levels of dopamine and other monoamines. Opioids opiate receptors in VTA decrease the activity of inhibitory GABA interneurons, subsequently resulting in a greater release of dopamine in forebrain regions

Other drugs, including nicotine and cannabinoids, lead to enhanced dopamine release through the activation of their respective receptors and subsequent disinhibition or excitation of dopamine neurons.

Pathways That Underlie Relapse

PFC NA VP

EXT AMY

BLA

VTA

Conditioned Cue-Induced Relapse

Through a process of associative learning, previously neutral stimuli acquire incentive-motivational properties during repeated pairings with consumption of an abused drug. These drug-associated stimuli subsequently elicit subjective drug desire and physiological arousal in a manner that perpetuates a return to further drug use

In the animal model several lines of research have extensively implicated cortico-striato-limbic pathways in the development and maintenance of drugcue associations that drive drugseeking behavior after periods of withdrawal.

Of particular interest has been the amygdala,. Excitotoxic lesions of the basolateral amygdala have no effect on cocainetaking during daily cocaine selfadministration

But these lesions completely abolish the reinstatement of cocaine-seeking produced by cocaine-paired cues long after the cessation of cocaine selfadministration Other studies have examined drugseeking after reversible forms of neuronal inactivation of discrete brain regions with sodium channel blockers or GABA receptor agonists.

Studies have demonstrated that the amygdalar mediation of conditionedcued reinstatement is dopaminedependent, Intrabasolateral amygdala blockade of D1 receptors abolishes cue-induced reinstatement, while enhancing dopamine levels in the amygdala during cue presentation will potentiate cocaine-seeking.

Recent studies have implicated the amygdala in the acquisition and consolidation of drugcue associations. Amygdalar disruption during the memory reconsolidation of previously learned cues will abolish cue-induced relapse.

Other brain regions involved in conditioned-cued reinstatement include discrete subregions of the prefrontal cortex and striatum. Pharmacological inactivation of the dorsal medial PFC, lateral OFC, or the nucleus accumbens core subregion significantly attenuates cue-induced cocaine-seeking.

Drug-induced adaptive changes in the circuitry that drives stimulusresponse (SR) learning, in particular the dorsal regions of the striatum (caudate and putamen), which are known to mediate habitual responses acquired by the strengthening of SR associations.

It has been well-established that psychostimulant administration produces the most notable changes in gene expression in the dorsal striatum, in contrast to the lesser degree of changes observed in the ventral striatum. Furthermore, the caudate-putamen receives the densest innervation by dopamine afferents.

In rodent models, extracellular dopamine in the caudate-putamen is increased during response for a cocaine-associated cue, while inactivation of the caudate-putamen by pharmacological means blocks response for cocaine-associated cues or context.

Recent studies PET in cocainedependent subjects during cueinduced craving have shown that dopamine in the caudate-putamen, but not in the ventral striatum ie NA is positively correlated with self-reports of craving.

In sum, a growing body of evidence supports the idea of long-term changes in striatal circuitry, whereby the caudate-putamen critically mediates habitual patterns of drugseeking at the time of relapse.

Drug-Primed Reinstatement

Small doses of an abused drug can initiate 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

Prelimbic cortex, NA core, and ventral pallidum are also involved in drug induced reinstatement

Neurotransmitter projections may drive cocaine-primed reinstatement, including dopaminergic inputs to the infralimbic cortex and NA shell.

Role of cortical glutamatergic projections to the NA has been established as a primary mechanism in drug-primed reinstatement of drugseeking.

Stress-Induced Reinstatement

Stress clearly plays a role in acquisition, maintenance, and relapse with drugs of abuse.

Stress in rats (usually footshock presented in the drug-paired context) has been commonly used to study stress-induced reinstatement of drugseeking..

Examination of the pathways that mediate footshock-induced stress have shown that some of the same circuitry required for conditioned-cued or drug-primed reinstatement of cocaine-seeking is also necessary for stress-induced reinstatement, including the prelimbic cortex and nucleus accumbens

Inactivation of extended amygdala structures, including the central amygdala and bed nucleus of the stria terminalis, will attenuate stressinduced reinstatement, while basolateral amygdala inactivation fails to block stressinduced reinstatement

The withdrawal/negative affect stage consists of key motivational elements such as: chronic irritability, emotional pain, malaise, dysphoria, alexithymia, and loss of motivation for natural rewards, characterized in animals by increases in reward thresholds during withdrawal from all major drugs of abuse.

Significant plasticity occurs in the neurotransmitter 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) occur that temporally precede and highly correlate with escalation in drug intake

During acute withdrawal, there is decreased activity of the reward systems as well as decreased opioid peptide, GABA, glutamate, and neuropeptide Y activity in elements of the extended amygdala and/or nucleus accumbens

However, as dependence and withdrawal develop, brain antireward systems such as corticotropinreleasing factor (CRF), norepinephrine, and dynorphin are recruited

Withdrawal: Corticotrophin Releasing Factor (CRF) Involvement

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

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

Heart rate Blood pressure Blood glucose

Response to stressors

For example, extracellular CRF in the extended amygdala is increased during acute withdrawal from drugs of abuse, and critically, CRF antagonists block excessive drug-taking during dependence

The observation that CRF receptor antagonists in the amygdala can block excessive drug intake associated with the development of dependence provides a compelling example of a key aspect of the plasticity of the extended amygdala in the development of addiction.

The development of the aversive emotional state that drives the negative reinforcement of addiction may also contribute to the critical problem in drug addiction of chronic relapse, where addicts return to compulsive drug-taking long after acute withdrawal

Central infusions of corticotropinreleasing factor (CRF) produce reinstatement, while elimination of the corticosterone response by surgical means or CRF receptor antagonists blocks stress-induced reinstatement, as do noradrenergic 2 receptor agonists, such as clonidine or lofexidine.

Administration of the -adrenergic receptor antagonist yohimbine produced a modest increase in cocaine- or methamphetamineseeking in rats when administered alone.

Yohimbine treatment has been shown to produce anxiety-like states in humans and laboratory animals, presumably through its activation of norepinephrine release. Yohimbine also has been reported to induce subjective craving in drugdependent subjects.

This effect suggests that stress may sensitize an individual to be more attentive to drug-paired cues, increase the incentive salience of the cues, or perhaps increase motivation to reduce negative affect states through renewed drug use.

CONCLUSION
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)

The classic anatomical areas of the brain involved in the reward pathway include the nucleus accumbens, ventral tegmental area and the prefrontal cortex Dopaminergic activity is the final chemical action in most behaviours relating to reward

Drugs of abuse may work with receptors 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.