There has been a recent renewal of interest in the therapeutic potential of serotonergic psychedelics. Here, we uncover the essential role of ventral hippocampus (vHpc) GABAergic interneurons in the anxiolytic effect evoked by the serotonergic psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI). Integrating anatomical, pharmacological, and genetic approaches, we show that 5-HT2A receptors in the CA1/subiculum (CA1/sub) region of the vHpc are required for the anxiolytic action of DOI. In vivo electrophysiology and opto-tagging experiments indicate that DOI enhances the firing rate of hippocampal fast-spiking parvalbumin (PV)-positive interneurons, most of which express the 5-HT2A receptors. Restoration of 5-HT2A receptors in PV-positive interneurons in a loss-of-function background reinstated the anxiolytic responses evoked by DOI in the vHpc CA1/sub region. Collectively, our results localize the acute anxiolytic action of a serotonergic psychedelic to 5-HT2A receptors in the ventral hippocampus and specifically identify PV-positive fast-spiking cells as a cellular trigger for the psychedelic-induced relief of anxiety-like behavior.

中文翻译：

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腹侧海马细小白蛋白中间神经元对血清素能迷幻 DOI 的急性抗焦虑作用产生门控


最近，人们对血清素能迷幻药的治疗潜力重新产生了兴趣。在这里，我们揭示了腹侧海马体 （vHpc） GABA 能中间神经元在血清素能迷幻药 2,5-二甲氧基-4-碘苯丙胺 （DOI） 引起的抗焦虑作用中的重要作用。整合解剖学、药理学和遗传学方法，我们表明 vHpc 的 CA1/subiculum （CA1/sub） 区域的 5-HT2A 受体是 DOI 的抗焦虑作用所必需的。体内 电生理学和光标记实验表明，DOI 提高了海马快速尖峰小白蛋白 （PV） 阳性中间神经元的放电率，其中大多数表达 5-HT2A 受体。在功能丧失背景下 PV 阳性中间神经元中 5-HT2A 受体的恢复恢复了 DOI 在 vHpc CA1/亚区诱发的抗焦虑反应。总的来说，我们的结果定位了血清素能迷幻药对腹侧海马体 5-HT2A 受体的急性抗焦虑作用，并特异性地确定了 PV 阳性快速刺激细胞是迷幻药诱导的缓解焦虑样行为的细胞触发因素。