Involvement of orexin-2 receptor in the ventral tegmental area in stress- and drug priming-induced reinstatement of conditioned place preference in rats.

Orexin neurons originate from the lateral hypothalamus and send their projections broadly throughout the central nervous system including to the ventral tegmental area (VTA). In the current study, the reinstatement model has been used to examine the effects of intra-VTA administration of TCS-OX2-29, an orexin-2 receptor (OX2R) antagonist, on drug priming- and forced swim stress (FSS)-induced reinstatement of morphine-induced conditioned place preference (CPP). A total of 73 adult male Wistar rats weighing 200-280 g were bilaterally implanted with cannulas into the VTA. For induction of CPP, subcutaneous (sc) injection of morphine (5 mg/kg) was done daily during a 3-day conditioning phase. After a 24-h "off" period following achievement of extinction criterion, the rats were tested for drug priming-induced reinstatement with a priming dose of morphine (1 mg/kg;sc) or after application of FSS on the reinstatement day. The animals then received different doses of the OX2R antagonist, TCS-OX2-29 (0.3,3,1 and 10 nM) bilaterally in the VTA (0.3 μl/side) and were tested for FSS- and morphine priming-induced reinstatement of CPP. Our findings indicate that intra-VTA administration of OX2R antagonist suppresses FSS and morphine priming-induced reinstatement in a dose-dependent manner. The role of the orexinergic system in morphine-induced reinstatement through activation of OX2R in the VTA provides evidence that the OX2R antagonist could be a useful therapeutic target for prevention of reinstatement of morphine-induced CPP.