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The current study determined for the first time the effect of vortioxetine on the <jats:italic>in vivo<\/jats:italic> firing of putative 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010INs whilst simultaneously recording pyramidal neuron activity using cortical slow\u2010wave oscillations as a readout. Extracellular single unit and local field potential recordings were made in superficial layers of the prefrontal cortex of urethane\u2010anaesthetised rats. 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010INs were identified by a short\u2010latency excitation evoked by electrical stimulation of the dorsal raphe nucleus (DRN). Juxtacellular\u2010labelling found such neurons had the morphological and immunohistochemical properties of 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010INs: basket cell or bipolar cell morphology, expression of 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010IN markers and parvalbumin\u2010immunonegative. Vortioxetine inhibited the short\u2010latency DRN\u2010evoked excitation of 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010INs and simultaneously decreased cortical slow wave oscillations, indicative of pyramidal neuron activation. Likewise, the 5\u2010HT<jats:sub>3<\/jats:sub>R antagonist ondansetron inhibited the short\u2010latency DRN\u2010evoked excitation of 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010INs. However unlike vortioxetine, ondansetron did not decrease cortical slow\u2010wave oscillations, suggesting a dissociation between this effect and inhibition of 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010INs. The 5\u2010HT reuptake inhibitor escitalopram had no consistent effect on any electrophysiological parameter measured. Overall, the current findings suggest that vortioxetine simultaneously inhibits (DRN\u2010evoked) 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010INs and excites pyramidal neurons, thereby changing the excitatory:inhibitory balance in cortex. However, under the current experimental conditions, these two effects were dissociable with only the former likely involving a 5\u2010HT<jats:sub>3<\/jats:sub>R\u2010mediated mechanism.<\/jats:p>","DOI":"10.1111\/ejn.15623","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T03:45:00Z","timestamp":1644551100000},"page":"1409-1423","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["<i>In vivo<\/i> electrophysiological study of the targeting of 5\u2010HT<sub>3<\/sub> receptor\u2010expressing cortical interneurons by the multimodal antidepressant, vortioxetine"],"prefix":"10.1111","volume":"55","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5968-3534","authenticated-orcid":false,"given":"Judith V.","family":"Schweimer","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of Oxford  Oxford UK"},{"name":"School of Psychology and Neuroscience University of 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