Requisite Role of Basolateral Amygdala Glucocorticoid Receptor Stimulation in Drug Context-Induced Cocaine-Seeking Behavior

Abstract

Background:Exposure to cocaine-associated stimuli triggers a robust rise in circulating glucocorticoid levels. Glucocorticoid receptors are richly expressed in the basolateral amygdala, a brain region that controls the reinstatement of cocaine-seeking behavior upon exposure to a previously cocaine-paired environmental context. In the present study, we investigated whether glucocorticoid receptor stimulation in the basolateral amygdala is integral to drug context-induced motivation to seek cocaine in a rat model of drug relapse.Methods:Rats were trained to lever press for cocaine reinforcement in a distinct environmental context and were then given daily extinction training sessions in a different context. At test, the rats received bilateral glucocorticoid receptor antagonist (mifepristone; 3 or 10ng/hemisphere) or vehicle microinfusions into either the basolateral amygdala or the overlying posterior caudate-putamen (anatomical control region). Immediately thereafter, drug-seeking behavior (i.e., nonreinforced lever presses) was assessed in the previously cocaine-paired context and locomotor activity was assessed in a novel context.Results:Intra-basolateral amygdala, but not intra-posterior caudate-putamen, mifepristone dose-dependently attenuated drug context-induced cocaine-seeking behavior relative to vehicle, such that responding was similar to that observed in the extinction context. In contrast, mifepristone treatment did not alter locomotor activity.Conclusions:These findings suggest that basolateral amygdala glucocorticoid receptor stimulation is necessary for drug context-induced motivation to seek cocaine.

Context-induced relapse after extinction versus punishment: similarities and differences

“…The results of this study demonstrate dissociable roles of the two amygdala subregions in context-induced relapse after extinction versus punishment. The BLA results of our study for context-induced relapse to drug seeking after extinction are consistent with results from previous studies (Chaudhri et al 2013 ; Fuchs et al 2005 ; Marinelli et al 2010 ; Stringfield et al 2016 ). Together, these results demonstrate that the amygdala’s role in context-induced relapse critically depends on the method used to achieve abstinence.…”

Drug-Induced Glucocorticoids and Memory for Substance Use

“…This hypothesis is supported by the critical involvement of the amygdala in CPP (reviewed earlier). Similarly, both the BLA (particularly GR receptors within the BLA; [145]) and hippocampus contribute to context-induced reinstatement of drug seeking [123], suggesting a role for cue-affect associations. More research is needed to probe the nature of memories formed for drug-related contexts, and test whether there is indeed a shift in the engagement of different memory systems.…”

“…In addition, after conditioning (with nicotine [142] or cocaine [143, 144]), drug-paired contexts directly evoked glucocorticoid responses. Blocking these glucocorticoid responses with a GR antagonist prior to cocaine-paired context exposure dose-dependently attenuated reinstatement of cocaine-seeking [145].…”

Role of glucocorticoid receptor-mediated mechanisms in cocaine memory enhancement

“…Adrenally secreted glucocorticoids (cortisol in humans, corticosterone in rats) potently modulate cocaine-induced behaviors, including cocaine self-administration and several forms of cocaine reinstatement (Deroche et al, 1997; Erb et al, 1998; Graf et al, 2013; Mantsch and Goeders, 1999; Stringfield et al, 2016). Moreover, glucocorticoids play an important role in memory storage by regulating intracellular signaling and gene transcription (Bamberger et al, 1996).…”