Cannabidiol attenuates methamphetamine-induced conditioned place preference in male rats and viability in PC12 cells through the Sigma1R/AKT/GSK3β/CREB signaling pathway

Background: Methamphetamine use is associated with several negative consequences, including neurotoxicity and greater probability of exhibiting a substance use disorder. Sigma1 receptor is involved in the neurobiological basis of several drug use disorders. Cannabidiol has received attention in the treatment of drug use disorders and neurotoxicity. Objectives: To investigate the effects of cannabidiol on methamphetamine-induced conditioned place preference (CPP) and the viability of PC12 cells. Methods: Adult male rats (n = 70) underwent methamphetamine (2 mg/kg, IP) induced CPP, and were administered cannabidiol (10, 20, 40, or 80 mg/kg, IP) during the methamphetamine withdrawal period for five consecutive days. Methamphetamine (0.5 mg/kg) was then injected to reactivate CPP. Four brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, and hippocampus) were extracted after the last test. PC12 cells were treated with cannabidiol, Sigma1R-siRNA, or BD1047 before methamphetamine exposure. Results: Administration of 20, 40, or 80 mg/kg cannabidiol facilitated CPP extinction (80 mg/kg, p Conclusions: Cannabidiol seems to inhibit the rewarding effects of methamphetamine and the effects of this drug on cell viability. Sigma1R should be given further consideration as a potential target for cannabidiol.背景：甲基苯丙胺（Methamphetamine）使用与多种不良后果相关，包括神经毒性（neurotoxicity）以及罹患物质使用障碍（substance use disorder）的概率升高。σ1受体（Sigma1 receptor）参与多种物质使用障碍的神经生物学基础机制。大麻二酚（cannabidiol）在物质使用障碍与神经毒性的治疗中受到广泛关注。 研究目的：探究大麻二酚对甲基苯丙胺诱导的条件性位置偏爱（Conditioned Place Preference, CPP）以及PC12细胞活力的影响。 方法：选取70只成年雄性大鼠，通过腹腔注射2 mg/kg剂量的甲基苯丙胺诱导条件性位置偏爱，并在甲基苯丙胺戒断期连续5天给予10、20、40或80 mg/kg剂量的大麻二酚腹腔注射（intraperitoneal, IP）。随后再次给予0.5 mg/kg的甲基苯丙胺以复现条件性位置偏爱。末次测试结束后，提取4个脑区组织：腹侧被盖区（ventral tegmental area）、伏隔核（nucleus accumbens）、前额叶皮层（prefrontal cortex）及海马体（hippocampus）。在甲基苯丙胺暴露处理前，分别用大麻二酚、σ1受体小干扰RNA（Sigma1R-siRNA）或BD1047处理PC12细胞。 结果：给予20、40或80 mg/kg剂量的大麻二酚可促进条件性位置偏爱消退（80 mg/kg组，p 结论：大麻二酚似乎可抑制甲基苯丙胺的奖赏效应及其对细胞活力的影响。σ1受体（Sigma1R）有望作为大麻二酚治疗的潜在靶点，值得进一步研究。