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.

Differential role of dopamine D3 receptor through balanced modulation of Akt/mTOR and ERK1/2 activity in the reactivation of cocaine rewarding memories evoked by psychological versus physiological stress

“…Nevertheless, these effects have been reported to be integrated in the ventral hippocampus and medial amygdala [38,40], which might explain the lack of activity observed in the DG and BLA during the reinstatement of cocaine-CPP induced by this stressor. On the other hand, the changes observed during the reactivation of the cocaine-seeking behaviour induced by restraint were concordant with those observed in these brain regions when the recall of rewarding memories of the drug was provoked by a psychosocial stressor [8].…”

“…25 mg/kg of cocaine dose has been previously shown to be adequate to induce a strong CPP [6][7][8]26]. On days 2 and 4, mice received firstly a saline injection before being confined to the vehicle-paired chamber and 4 h after placing them to the home cage, animals were injected with cocaine before confinement in the drug-paired chamber for another 30 min.…”

“…In addition, D3R blockade diminishes the availability of these receptors and, consequently, D3R-coupled biochemical pathways might be altered, as it has been published before [7,8,21]. D3R regulates the mitogen-activated protein kinase (MEK)signal-regulated kinases (ERK), phosphatidyl inositol 3-kinase (PI3K)-protein kinase B (Akt) and mechanistic target of rapamicine (mTOR) intracellular signalling [21].…”

Phenylalanine Rich Diet (Vicia faba L.) Enhances the Expression of Dopamine Receptor D3 (DRD3) Gene in Rabbits

“…The cycle of dopamine biosynthesis begins with the phenylalanine transformation process by phenylalanine hydroxylase enzyme (PAH) and ends at the binding of dopamine to DRD3 in the brain. The DRD3 is the most important receptor for dopamine [31], [34], [35]. The steps of dopamine biosynthesis cycle in rabbits are the same in humans [43].…”

“…The cycle of dopamine biosynthesis begins with the phenylalanine transformation process by phenylalanine hydroxylase enzyme (PAH) and ends at the binding of dopamine to DRD3 in the brain. Then dopamine comes out of the cerebral membrane to the rest of the body [34]. The Dopamine Receptor D3 (DRD3) is the most important receptor for dopamine [9], [31], [35].…”