Cheng Ying-Jie, Zan Gui-Ying, Deng Ying-Zhi, Deng Di, Wu Man-Qing, Chai Jing-Rui, Wang Yu-Jun, Liu Jing-Gen, Zhao Min
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Nat Commun. 2025 May 23;16(1):4808. doi: 10.1038/s41467-025-59859-z.
Methamphetamine (METH) is a highly addictive psychostimulant, yet its addiction mechanisms remain unclear. Oxytocin (OXT), a neuropeptide, shows promise in reducing METH addiction, but how OXT exerts its effects is poorly understood. Using conditioned place preference (CPP), we first found that intranasal OXT other than Arginine Vasopressin (AVP) administration suppressed METH-CPP in mice, which could be reversed by OXT receptors (OXTRs) blockade in the nucleus accumbens (NAc) core. Activating OXTRs in the NAc core similarly reduced METH-CPP. Then, we found repeated METH exposure inhibited oxytocinergic neurons within the paraventricular nucleus (PVN) and lowered PVN OXT protein level. Chemogenetic activation of PVN oxytocinergic neurons (PVN) blocked METH-CPP. Furthermore, METH inhibited PVN-NAc core circuit other than PVN-NAc shell circuit. Activation of PVN-NAc core circuit significantly inhibited METH-CPP. This study reveals METH may impair the endogenous OXT system, especially the PVN-NAc core circuit, highlighting OXT's therapeutic potential for METH use disorder (MUD).
甲基苯丙胺（METH）是一种极易成瘾的精神兴奋剂，但其成瘾机制仍不清楚。催产素（OXT）作为一种神经肽，在减轻甲基苯丙胺成瘾方面显示出前景，但人们对催产素如何发挥其作用却知之甚少。通过条件性位置偏爱（CPP）实验，我们首先发现，与精氨酸加压素（AVP）不同，经鼻给予催产素可抑制小鼠的甲基苯丙胺诱导的CPP，而伏隔核（NAc）核心区域的催产素受体（OXTRs）阻断可逆转这种抑制作用。激活NAc核心区域的OXTRs同样可降低甲基苯丙胺诱导的CPP。然后，我们发现反复给予甲基苯丙胺会抑制室旁核（PVN）内的催产素能神经元，并降低PVN中催产素蛋白水平。对PVN催产素能神经元进行化学遗传学激活可阻断甲基苯丙胺诱导的CPP。此外，甲基苯丙胺抑制的是PVN-NAc核心回路而非PVN-NAc壳核回路。激活PVN-NAc核心回路可显著抑制甲基苯丙胺诱导的CPP。本研究揭示，甲基苯丙胺可能损害内源性催产素系统，尤其是PVN-NAc核心回路，突出了催产素在治疗甲基苯丙胺使用障碍（MUD）方面的治疗潜力。
