Zhu Weili, Ding Zengbo, Zhang Zhihui, Wu Xiao, Liu Xiaoya, Zhang Ya, Li Suxia, Zhou Liping, Tian Geng, Qin Jing
National Institute on Drug Dependence, Peking University & Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
Department of Stomatology, Peking University Third Hospital, Beijing, China.
Front Neurosci. 2021 Sep 10;15:723064. doi: 10.3389/fnins.2021.723064. eCollection 2021.
Ketamine is a popular recreational substance of abuse that induces persistent behavioral deficits. Although disrupted oxytocinergic systems have been considered to modulate vulnerability to developing drugs of abuse, the involvement of central oxytocin in behavioral abnormalities caused by chronic ketamine has remained largely unknown. Herein, we aimed to investigate the potential role of oxytocin in the medial prefrontal cortex (mPFC) in social avoidance and cognitive impairment resulting from repeated ketamine administration in mice. We found that ketamine injection (5 mg/kg, i.p.) for 10 days followed by a 6-day withdrawal period induced behavioral disturbances in social interaction and cognitive performance, as well as reduced oxytocin levels both at the periphery and in the mPFC. Repeated ketamine exposure also inhibited mPFC neuronal activity as measured by a decrease in c-fos-positive cells. Furthermore, direct microinjection of oxytocin into the mPFC reversed the social avoidance and cognitive impairment following chronic ketamine exposure. In addition, oxytocin administration normalized ketamine-induced inflammatory cytokines including TNF-α, IL-6, and IL-1β levels. Moreover, the activation of immune markers such as neutrophils and monocytes, by ketamine was restored in oxytocin-treated mice. Finally, the reversal effects of oxytocin on behavioral performance were blocked by pre-infusion of the oxytocin receptor antagonist atosiban into the mPFC. These results demonstrate that enhancing oxytocin signaling in the mPFC is a potential pathway to reverse social avoidance and cognitive impairment caused by ketamine, partly through inhibition of inflammatory stimulation.
氯胺酮是一种常见的滥用娱乐性物质，会导致持续性行为缺陷。尽管催产素能系统紊乱被认为会调节对滥用药物形成的易感性，但中枢催产素在慢性氯胺酮引起的行为异常中的作用在很大程度上仍不清楚。在此，我们旨在研究催产素在内侧前额叶皮质（mPFC）中对小鼠反复注射氯胺酮所致社交回避和认知障碍的潜在作用。我们发现，连续10天腹腔注射氯胺酮（5毫克/千克），随后停药6天，会导致社交互动和认知表现出现行为障碍，同时外周和mPFC中的催产素水平降低。反复接触氯胺酮还通过c-fos阳性细胞数量减少来衡量，抑制了mPFC神经元活动。此外，将催产素直接微量注射到mPFC中可逆转慢性氯胺酮暴露后的社交回避和认知障碍。此外，给予催产素可使氯胺酮诱导的炎性细胞因子（包括TNF-α、IL-6和IL-1β）水平恢复正常。此外，在接受催产素治疗的小鼠中，氯胺酮对中性粒细胞和单核细胞等免疫标志物的激活作用得到恢复。最后，在mPFC中预先注入催产素受体拮抗剂阿托西班可阻断催产素对行为表现的逆转作用。这些结果表明，增强mPFC中的催产素信号传导是一条潜在途径，可部分通过抑制炎症刺激来逆转氯胺酮引起的社交回避和认知障碍。
