Ventral hippocampal parvalbumin interneurons gate the acute anxiolytic action of the serotonergic psychedelic DOI

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. [Display omitted] •The psychedelic DOI evokes acute anxiolytic effects in rodent models via the vHpc•DOI enhances the firing rate of a fast-spiking neuron subpopulation in the vHpc•Opto-tagging reveals that DOI recruits PV-positive inhibitory interneurons in the vHpc•Agonism of 5-HT2A receptors on PV neurons in the vHpc mediates DOI-evoked anxiolysis Tiwari et al. identify the discrete neural circuit underlying the acute anxiolytic actions of the serotonergic psychedelic DOI, demonstrating that DOI recruits 5-HT2A receptors on parvalbumin-positive, fast-spiking inhibitory interneurons in the ventral hippocampal CA1/subiculum region to drive its acute anxiolytic effects.