Hypocretin/orexin system in the nucleus accumbens as a promising player in the extinction and reinstatement of methamphetamine-induced CPP

Abstract

One of the main obstacles in treating psychostimulant addiction is relapse even after long-term abstinence. The nucleus accumbens (NAc) is located in the basal forebrain, responsible for regulating several behaviors, specifically reward-related effect of psychostimulants. In the current study, an unbiased place conditioning paradigm was performed to inquire the role of the hypocretin/orexin system in the NAc in the extinction and reinstatement of methamphetamine (Meth)-induced conditioned place preference (CPP). Similar to previous investigations, rats were conditioned with Meth (1 mg/kg; sc) for five consecutive days to elicit CPP. The rats underwent Meth conditioning protocol received SB334867 or TCS OX2 29, an orexin receptor 1 (OXr1) antagonist or orexin receptor 2 (OXr2) antagonist (0, 3, 10, and 30 nmol/0.5 μL DMSO %12) in the NAc during the extinction period to elucidate the role of OXrs on the extinction of Meth-induced CPP. Meanwhile, extinguished rats received SB334867 or TCS OX2 29 (0, 1, 3, 10, and 30 nmol/0.5 μL DMSO %12) in the NAc prior to an effective priming dose of Meth to evaluate the impact of OXr antagonists on the reinstatement of Meth-induced CPP. The current data pointed out intra-NAc microinjection of SB334867 or TCS OX2 29 blocked both extinction and reinstatement of Meth-induced CPP. In addition, the OXr1 antagonist was more potent than the OXr2 antagonist to suppress both extinction and reinstatement phases of Meth-induced CPP. Based on the current data, the OX system in the NAc is extensively implicated in the reward properties of Meth; therefore, modulation of this system has therapeutic potential in treating psychostimulant use disorders.