NEUROBIOLOGY OF A RELAPSE!

Learning Processes Underlying Drug Addiction (N. White, 1996). (Dr.V. Sakhar)

Amygdala-NAc (Incentive) – promotes approach to and interaction with drug related cues (produces behavior unconsciously)

Caudate-Putamen (Habit) – promotes repetition of behaviors performed in the presence of drug-related stimuli (produces behavior unconsciously)

Hippocampus (Declarative) – promotes focusing of cognitive processes on drug related situations (conscious)

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 which will lead to relapse.

 Particular interest has been the amygdala ( affective learning ).

 Lesions of the amygdala (basolateral amygdala) have no effect on cocaine-taking during daily cocaine self-administration, but these lesions completely abolish the reinstatement of cocaine

seeking produced by cocaine-paired cues long after the cessation of cocaine self-administration.

 Additional studies have demonstrated that the amygdalar mediation of conditioned-cued reinstatement is dopamine

dependent, in that intrabasolateral amygdala blockade of dopamine D1 receptors abolishes cue-induced reinstatement, while enhancing dopamine levels in the amygdala during cue presentation will potentiate cocaine-seeking.

 Other brain regions involved in conditioned-cued reinstatement include discrete subregions of the prefrontal cortex and striatum.

 Pharmacological inactivation (either by sodium channel blockade or GABA receptor agonists) of the dorsal medial prefrontal cortex (anterior cingulate and prelimbic cortex), the lateral orbitofrontal cortex, or the nucleus accumbens core significantly attenuates cue-induced cocaineseeking.

 IN VIVO HUMAN imaging methods : cocaine-paired cues have been shown to increase metabolic activation of the amygdala, the anterior cingulate region of the cortex, the nucleus accumbens, and the orbitofrontal cortex. Because addiction is by definition “habitual,” recent attention has turned to the study of drug-induced adaptive changes in particular the dorsal striatum (caudate and putamen), which are known to mediate habitual responses. The caudate-putamen receives the densest innervation by dopamine afferents. In rodent models, extracellular dopamine in the caudateputamen is increased during response for a cocaineassociated cue, while inactivation of the caudate-putamen by pharmacological means blocks response for cocaine

associated cues. Positron emission tomography in cocaine-dependent subjects during cue-induced craving have shown that INCREASED dopamine in the caudate-putamen. Clinical evidence has clearly established the ability of drug

associated environmental cues (i.e., associated drug paraphernalia or locations where a drug was previously consumed) to elicit drug craving and consequently reinstate drug-seeking and drug-taking. Conditioned-cued responses have been demonstrated for a variety of drugs of abuse, including psychostimulants, opiates, nicotine, and alcohol. EG: abstinent cocaine abusers report intense subjective craving and autonomic arousal when exposed to cocaine

paired stimuli, such as white powder, individuals with whom they shared the cocaine-taking experience, and other conditioned stimuli. Drug-Primed Reinstatement

 Similar to conditioned-cued reinstatement, a number of studies have examined drug-primed reinstatement in the animal model of relapse

 The prelimbic cortex, nucleus accumbens core, and ventral pallidum necessary for cocaine-primed reinstatement.

 One notable contrast in the neural circuitry underlying drugprimed versus conditioned-cued reinstatement of cocaine

seeking is the fact that amygdala inactivation has no effect on cocaine-primed reinstatement. (no role of amygdala)

 Additional evidence suggests that other neurotransmitter projections may drive cocaine-primed reinstatement, including dopaminergic inputs to the infralimbic cortex and nucleus accumbens shell.

 a critical role of cortical glutamatergic projections to the nucleus accumbens has been established as a primary mechanism in drug-primed reinstatement of drug-seeking.

Reference Credits: Dr. V Sakhar, Neurobiology of Addcition