Psychostimulant addiction is a chronic brain disorder with high relapse rates, requiring new therapeutic strategies. The orexin system is highly implicated in processing reward and addiction through connections with critical areas such as the hippocampus. This study investigated the role of orexin-1 receptors (OX1R) within the CA1 subregion of the hippocampus in the extinction and reinstatement of the methamphetamine-induced conditioned place preference. After cannulae implantation, recovery, and establishing the methamphetamine place preference, 98 male Wistar rats received different doses of bilateral intra-CA1 selective OX1R antagonist, SB334867 (1, 3, 10, and 30 nmol/0.5 μl DMSO per side) during the 10-day extinction period (daily) or after extinction phase, just on the reinstatement day (single dose) in separate experimental and control groups. The findings indicated that bilateral microinjection of SB334867 into the CA1 area during the extinction period could significantly reduce the extinction latency and maintenance of rewarding aspects of methamphetamine dose-dependently (3, 10, and 30 nmol). In another set of experiments, a single dose of bilateral intra-CA1 SB334867 administration on the reinstatement phase prevented the methamphetamine-induced reinstatement of drug-seeking behaviors at the high doses (10, and 30 nmol). The present study provided more evidence for the implication of hippocampal OX1R in the maintenance of rewarding and reinforcing properties of methamphetamine and its role in the relapse of methamphetamine-seeking behavior. Further investigations on the role of the orexin system, including the orexin-2 receptors in treating addiction, are needed to introduce its antagonists as effective therapeutic options for psychostimulant addiction.

精神兴奋剂成瘾是一种慢性脑部疾病，复发率高，需要新的治疗策略。食欲素系统通过与海马体等关键区域的连接，与处理奖赏和成瘾密切相关。本研究调查了食欲素 1 受体 (OX1R) 在海马 CA1 亚区内在甲基苯丙胺诱导的条件性位置偏爱的消失和恢复中的作用。在插管植入、恢复和建立甲基苯丙胺位置偏好后，98 只雄性 Wistar 大鼠在 10 个月内接受不同剂量的双侧 CA1 内选择性 OX1R 拮抗剂 SB334867（每侧 1、3、10 和 30 nmol/0.5 μl DMSO） -day 消光期（每日）或消光期后，就在单独的实验组和对照组的恢复日（单剂量）。研究结果表明，在消退期将 SB334867 双侧显微注射到 CA1 区域可以显着减少消退潜伏期和维持甲基苯丙胺的奖励方面，剂量依赖性（3、10 和 30 nmol）。在另一组实验中，在恢复阶段单剂量双侧 CA1 内 SB334867 给药可防止高剂量（10 和 30 nmol）下甲基苯丙胺诱导的寻药行为恢复。本研究为海马 OX1R 在维持甲基苯丙胺的奖励和强化特性及其在甲基苯丙胺寻求行为复发中的作用提供了更多证据。