Cai Jialing, Che Xiaohang, Xu Tianyu, Luo Yuanchao, Yin Meixue, Lu Xianda, Wu Chunfu, Yang Jingyu
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Exp Neurol. 2022 Jan;347:113907. doi: 10.1016/j.expneurol.2021.113907. Epub 2021 Oct 27.
Propensity to relapse, even after long-term abstinence, is a crucial feature of methamphetamine (METH) abuse. We and other laboratories have reported that acute treatment of oxytocin (OXT), a hormone and neuropeptide, could inhibit reinstatement of METH seeking in animal studies. However, the effects of repeated OXT treatment on METH reinstatement as well as underlying mechanisms are still unclear. In the present study, the effects of repeated OXT treatment during abstinence on context- or restraint stress-induced reinstatement were investigated using the mice conditioned place preference (CPP) paradigm. After three intermittent injections of METH (2 mg/kg, i.p.) to induce CPP, mice received a daily bilateral intra-hippocampus injection of OXT (0.625, 1.25 or 2.5 μg) for 8 consecutive days before the context- or restraint stress-induced reinstatement test. Meanwhile, adult hippocampal neurogenesis (AHN) level was detected using immunostaining. To further clarify the role of AHN underlying OXT's effects on METH-CPP reinstatement, temozolomide (TMZ, 25 mg/kg, i.p.) was employed to deplete AHN prior to OXT treatment. The data showed that repeated OXT treatment (1.25 and 2.5 μg, intra-hippocampus) significantly inhibited both context- and restraint stress-induced METH-CPP reinstatement and concomitantly promoted AHN in a dose-dependent manner. Notably, TMZ pre-treatment markedly abolished all the above-mentioned effects of OXT, suggesting that AHN was closely involved in OXT's inhibition on reinstatement induced by both triggers. Taken together, the present study indicated that repeated OXT treatment during abstinence could inhibit both context- and restraint stress-induced METH-CPP reinstatement possibly by promoting AHN in mice, which provided a better understanding for OXT's beneficial effects on METH addiction.
即使经过长期禁欲，复吸倾向仍是甲基苯丙胺（METH）滥用的一个关键特征。我们和其他实验室报告称，在动物研究中，对激素和神经肽催产素（OXT）进行急性治疗可抑制觅药行为的恢复。然而，重复给予OXT治疗对METH觅药行为恢复的影响及其潜在机制仍不清楚。在本研究中，我们使用小鼠条件性位置偏爱（CPP）范式，研究了禁欲期间重复给予OXT治疗对情境或束缚应激诱导的觅药行为恢复的影响。在通过三次间歇性注射METH（2mg/kg，腹腔注射）诱导CPP后，在情境或束缚应激诱导的觅药行为恢复测试前，小鼠连续8天每天双侧海马内注射OXT（0.625、1.25或2.5μg）。同时，使用免疫染色检测成年海马神经发生（AHN）水平。为了进一步阐明AHN在OXT对METH-CPP觅药行为恢复作用中的作用，在OXT治疗前使用替莫唑胺（TMZ，25mg/kg，腹腔注射）来消耗AHN。数据显示，重复给予OXT治疗（海马内注射1.25和2.5μg）可显著抑制情境和束缚应激诱导的METH-CPP觅药行为恢复，并以剂量依赖的方式促进AHN。值得注意的是，TMZ预处理显著消除了OXT的所有上述作用，表明AHN密切参与了OXT对两种触发因素诱导的觅药行为恢复的抑制作用。综上所述，本研究表明，禁欲期间重复给予OXT治疗可能通过促进小鼠的AHN来抑制情境和束缚应激诱导的METH-CPP觅药行为恢复，这为OXT对METH成瘾的有益作用提供了更好的理解。
