Distinct regulation of dopamine D3 receptor in the basolateral amygdala and dentate gyrus during the reinstatement of cocaine CPP induced by drug priming and social stress

Abstract

Relapse in cocaine seeking and intake is one of the main challenges when treating its addiction. Among the triggering factors for recurrence of cocaine use are the re-exposure to the drug and stressful events. Cocaine relapse engages the activity of memory-related nuclei, such as the basolateral amygdala (BLA) and the hippocampal dentate gyrus (DG), which are responsible for emotional and episodic memories. Besides, D3 receptor (D3R) antagonists have recently arisen as a potential treatment for preventing drug relapse. Thus, we have assessed the impact of D3R blockade in the expression of some dopaminergic markers and in the activity of the mTOR pathway, that is modulated by D3R, in the BLA and DG during the reinstatement of cocaine-induced CPP evoked by drug priming and social stress. Reinstatement of cocaine-CPP paralleled with a trend to increase of D3R and dopamine transporter (DAT) levels in the BLA. Social stress-but not drug-induced reactivation of cocaine memories was prevented by systemic administration of SB-277011-A (a selective D3R antagonist), that was able, however, to impede D3R and DAT up-regulation in the BLA during CPP reinstatement evoked by both stress and cocaine. Concomitantly with cocaine-CPP reactivation occurred a diminution of mTOR phosphorylation (activation) in the BLA and DG that was inhibited by D3R blockade in both nuclei before the social stress episode, and only in the BLA when CPP reinstatement was provoked by a cocaine prime. Our data, while support a main role for D3R signalling in the BLA in the reactivation of cocaine memories evoked by social stress, indicates that different neural circuits and signalling mechanisms might mediate in the reinstatement of cocaine-seeking behaviours depending upon the triggering stimuli.