Compulsive Drug‐Seeking Behavior and Relapse

Abstract

The development of addiction and vulnerability to relapse following withdrawal is proposed to be the result of neuroadaptive processes within the central nervous system that oppose the acute reinforcing actions of drugs of abuse. These changes lead to impairment in the mechanisms that mediate positive reinforcement and the emergence of affective changes such as anxiety, dysphoria, and depression during withdrawal. Considerable evidence exists implicating perturbations in DA and 5‐HT transmission in the nucleus accumbens—neurochemical systems that are activated by cocaine and ethanol self‐administration and deficient during withdrawal—as potential substrates for these affective changes. In addition, growing evidence suggests that enhanced CRF release in the central nucleus of the amygdala represents a mechanism underlying the anxiogenic and stress‐like consequences of withdrawal that are common to all drugs of abuse. A growing body of evidence also implicates dysregulation of the non‐neuroendocrine CRF stress system within the central nucleus of the amygdala as a common factor in the anxiogenic and aversive consequences of withdrawal from drugs of abuse. Moreover, a possible link may exist between long‐lasting abnormalities in CRF function in the CeA and vulnerability to relapse during protracted abstinence. Another presumably critical element contributing to the chronic relapsing nature of drug addiction is the learned responses to drug‐related stimuli. The long‐lasting efficacy of drug‐ and alcohol‐associated contextual stimuli in eliciting drug‐seeking behavior in animal models of relapse resembles the endurance of conditioned cue reactivity and cue‐induced cocaine craving in humans and confirms a significant role of learning factors in the long‐lasting addictive potential of cocaine. With cocaine, D1‐dependent neural mechanisms within the medial prefrontal cortex and basolateral amygdala may be important substrates for the motivating effects of drug‐related environmental stimuli. With ethanol, available data suggest a role for opioid receptors in the mediation of conditioned drug‐seeking behavior. Finally, conditioning factors (i.e., exposure to drug‐associated stimuli) and stress can interact to augment vulnerability to relapse. This finding emphasizes that it will be important to consider the simultaneous effects of multiple environmental triggers for relapse in the development of treatment and medication strategies.

CRF–CRF 1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats

“…The CRF system has been implicated in anxiety-like behavior, and studies of CRF 1 receptor antagonists have promising potential for anxiolytic drug development (13). Our findings with nicotine add to reports showing increased amygdalar CRF release, and anxiety-like behaviors following withdrawal from other drugs of abuse, including ethanol, cocaine, opiates, and cannabinoids (27)(28)(29)(30)(31)(32), and suggest that overactivation of the extrahypothalamic CRF-CRF 1 system may constitute a common denominator of motivational aspects of drug withdrawal. Overactivation of the CRF-CRF 1 system during withdrawal is also associated with a hypoactivation of the dopaminergic system in the central nucleus of the amygdala (33), suggesting that both systems may interact to mediate anxiety-like behavior during withdrawal.…”

A Stress-Induced Shift From Trace to Delay Conditioning Depends on the Mineralocorticoid Receptor

“…For example, anxiety or stress can lead to relapse in drug addiction (67,68), and it is conceivable that this might hold for obsessive-compulsive disorder, too. The shift might also have implications for posttraumatic stress disorder, which is assumed to result from excessive fear learning under stress and is characterized by impaired hippocampal functioning (49).…”

Effects of Psychotropic Agents on Extinction of Lever-Press Avoidance in a Rat Model of Anxiety Vulnerability

“…Hypoactive mPFC and hyperactive limbic system, including nucleus accumbens (NAc) and amygdala, are susceptibility factors in psychopathology of anxiety disorders (Milad et al, 2006; Rauch et al, 2006). Historically, dysfunctional catecholamine transmission in the mPFC and NAc has been associated with abnormal active-avoidance behavior and implicated in anxiety pathology (Giorgi et al, 1994; Duncan et al, 1996; Lacroix et al, 1998; Weiss et al, 2001). However, results in rodents are inconsistent due to the wide variety of animal models, behavioral procedures and techniques employed.…”