Chen Lihua, Kreko-Pierce Tabita, Cassoday Stefanie L, Al-Harthi Lena, Hu Xiu-Ti
Department of Microbial Pathogens and Immunity, RUSH University Medical Center, Chicago, IL, United States.
Front Pharmacol. 2025 Feb 14;16:1527795. doi: 10.3389/fphar.2025.1527795. eCollection 2025.
Methamphetamine (Meth) is one of the most widely used illicit drugs worldwide, exerting potent psychostimulant effects that fuels its highly addictive nature. Chronic Meth use is associated with severe cognitive impairments, particularly in executive functions, decision-making, and working memory, which persist long even after cessation of Meth use. These cognitive deficits are associated with dysfunction of glutamatergic pyramidal neurons in the medial prefrontal cortex (mPFC), which regulates addiction and cognition. Both human and animal studies highlight Meth-induced mPFC dysfunction that contributes to compulsive behaviors and relapse. Emerging evidence also highlights significant sex differences in Meth use disorder (MUD). Previous studies suggest that Meth-induced behavioral and neuronal dysfunctions are different between males and females, but the cellular and molecular mechanism are not fully understood. Using behavioral and electrophysiological approaches (whole-cell patching), this study determined certain sex differences in neuronal dysfunction in the mPFC of rats that self-administered Meth (Meth-SA) followed by a short (2-5 d) or long-term (≥30 d) withdrawal. We found that both male and female rats self-administered methamphetamine in a similar pattern; however, the resulting hypoactivity, hyperactivity, and calcium dysregulation in mPFC neurons differed between the sexes. Such sex-specific neuronal dysfunction was associated with, and depended on, short or long-term withdrawal, respectively. By understanding these sex-specific behavioral/neuronal differences following different Meth withdrawal period, our novel findings demonstrate the role of sex as a biological variable in Meth-use and relapse, and reveal the effects of drug-using environment on mPFC neuronal dysfunction during withdrawal, providing insights for gender-specific treatment strategies.
甲基苯丙胺（冰毒）是全球使用最广泛的非法药物之一，具有强大的精神刺激作用，这加剧了其高度成瘾性。长期使用冰毒与严重的认知障碍有关，尤其是在执行功能、决策和工作记忆方面，即使在停止使用冰毒后，这些障碍仍会长期存在。这些认知缺陷与内侧前额叶皮质（mPFC）中谷氨酸能锥体神经元功能障碍有关，该区域调节成瘾和认知。人类和动物研究均强调了冰毒诱导的mPFC功能障碍会导致强迫行为和复发。新出现的证据还突出了冰毒使用障碍（MUD）中显著的性别差异。先前的研究表明，冰毒诱导的行为和神经元功能障碍在雄性和雌性之间存在差异，但细胞和分子机制尚未完全了解。本研究采用行为学和电生理学方法（全细胞膜片钳），确定了自行注射冰毒（Meth-SA）后短期（2-5天）或长期（≥30天）戒断的大鼠mPFC神经元功能障碍中的某些性别差异。我们发现，雄性和雌性大鼠自行注射甲基苯丙胺的模式相似；然而，mPFC神经元由此产生的活动减退、活动亢进和钙调节异常在性别之间存在差异。这种性别特异性的神经元功能障碍分别与短期或长期戒断有关，并取决于短期或长期戒断。通过了解不同冰毒戒断期后的这些性别特异性行为/神经元差异，我们的新发现证明了性别作为生物变量在冰毒使用和复发中的作用，并揭示了戒毒环境对戒断期间mPFC神经元功能障碍的影响，为针对性别差异的治疗策略提供了见解。
