Evidence for conditional neuronal activation following exposure to a cocaine-paired environment: role of forebrain limbic structures

Abstract

The reinforcing properties of cocaine can readily become associated with salient environmental stimuli that acquire secondary reinforcing properties. This form of classical conditioning is of considerable clinical relevance as intense craving can be evoked by the presentation of stimuli previously associated with the effects of cocaine. To understand better the neurobiology of cocaine-induced environment-specific conditioning, Fos expression was examined in the forebrain of rats exposed to an environment in which they had previously received cocaine. These results were compared to those observed following an acute injection of cocaine. Consistent with its stimulant actions, cocaine produced an increase in locomotion that was accompanied by an increase in Fos expression within specific limbic regions (cingulate cortex, claustrum, piriform cortex, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and amygdala) as well as the basal ganglia (dorsomedial striatum and nucleus accumbens). Exposure of rats to the cocaine-paired environment also produced an increase in locomotion, as compared to various control groups. In addition to this behavioral effect, conditioned subjects exhibited a significant increase in Fos expression within the cingulate cortex, claustrum, lateral septal nucleus, paraventricular nucleus of the thalamus, lateral habenula, and the amygdala, suggesting increased neuronal activity within these regions. In contrast to the dramatic effects observed within these structures, no conditional activation was observed within the piriform cortex, nucleus accumbens, or dorsal striatum, suggesting that these brain areas are not involved in the conditioned response. The present findings indicate that specific limbic regions exhibit increased neuronal activation during the presentation of cocaine-paired cues and may be involved in the formation of associations between cocaine's stimulant actions and the environment in which the drug administration occurred. Although the nucleus accumbens is necessary for the reinforcing and locomotor effects of cocaine, it does not exhibit a conditional Fos response, suggesting that different neural circuits are involved in the unconditioned and conditioned effects of cocaine.

Context-specific Enhancement of Glutamate Transmission by Cocaine

“…The occurrence of these cocaine-induced effects only in the presence of environmental stimuli previously paired with repeated cocaine administration indicates a role for glutamate transmission in the nucleus accumbens in the environmental regulation of cocaine-induced behavior. In support of this notion, the elicitation of locomotor activity in experimental animals and of craving in cocaine addicts by cocaine-conditioned cues is associated with increased metabolism in cortical nuclei having glutamatergic projections to the nucleus accumbens (Brown et al 1992;Grant et al 1996;Childress et al 1999). Taken together these data are consistent with a role for corticofugal glutamatergic afferents to the nucleus accumbens in modulating cocaine-induced motor activity by environmental stimuli.…”

The Role of Acetylcholine in Cocaine Addiction

“…The amygdala is one of the few brain regions that consistently exhibit increased metabolic activity in response to cocaine-associated cues in both animal (Brown et al, 1992;Ciccocioppo et al, 2001) and human (Childress et al, 1999;Kilts et al, 2001) studies, consistent with this region's role in conditioned emotional memories. In preclinical studies, the infusion of scopolamine into the BLA just prior to the acquisition phase of a classical conditioning procedure produced a dose-dependent disruption of cocaine-seeking behavior during cue-induced drug reinstatement (See et al, 2003).…”

Relapse to cocaine seeking increases activity-regulated gene expression differentially in the prefrontal cortex of abstinent rats

“…1991;Moratalla et al 1992;Bhat and Baraban 1993; McGinty 1994, 1995;Fosnaugh et al 1995;Tan et al 2000;Grimm et al 2003;Le Foll et al 2005;Fumagalli et al 2006). Furthermore, cocaine-associated cues activate IEGs (Brown et al 1992;Crawford et al 1995;Everitt and Robbins 2000;Ciccocioppo et al 2001;Thomas et al 2003). Most relevant to the present study, re-exposure to an environment previously associated with cocaine self-administration, with or without a priming injection following prolonged cocaine abstinence, resulted in enhanced Fos protein expression within the anterior cingu-late, nucleus accumbens, basolateral amygdala, hippocampal formation, and central grey (Neisewander et al 2000).…”