Distinct roles for orexin-1 and orexin-2 receptors in the dentate gyrus of the hippocampus in the methamphetamine-seeking behavior in the rats

Because of the relapsing properties of psychostimulants such as methamphetamine (Meth), there is no estab-lished pharmacotherapy for Meth addiction. The orexinergic system is a promising target for treating psychos-timulant use disorders and relapse. However, to the best of our knowledge, no investigation regarding the role of orexin receptors in the dentate gyrus (DG) region of the hippocampus has been conducted in the extinction and reinstatement of Meth-seeking behavior. Two stainless-steel guide cannulae were bilaterally implanted into the DG of the rats' brains. The unbiased conditioned place preference (CPP) procedure was conducted to induce Meth conditioning. Following the five days Meth injections (1 mg/kg; sc), animals received intra-DG microinjection of SB334867 or TCS OX2 29, as orexin 1 (OX1) or orexin 2 (OX2) receptor antagonists, respectively (without Meth administration) during extinction phase to elucidate the role of orexin receptors in the latency of the extinction period in the Meth-conditioned rats. To evaluate the role of orexin receptors in the DG region in the reinstate-ment of Meth-seeking behavior, the extinguished rats received SB334867 or TCS OX2 29 before injecting a priming dose of Meth (0.25 mg/kg; sc). The results indicated two distinct roles for the OX1 and OX2 receptors in the DG region. TCS OX2 29 attenuated the extinction latency, and SB334867 considerably reduced the rein-statement of Meth-seeking behavior in this region. Therefore, the DG region's orexinergic system might be a potential therapeutic target for psychostimulant use disorders.