In vivo electrophysiological study of the targeting of 5‐HT 3 receptor‐expressing cortical interneurons by the multimodal antidepressant, vortioxetine

The antidepressant vortioxetine has high affinity for the ionotropic 5‐HT 3 receptor (5‐HT 3 R) as well as other targets including the 5‐HT transporter. The procognitive effects of vortioxetine have been linked to altered excitatory:inhibitory balance in cortex. Thus, vortioxetine purportedly inhibits cortical 5‐HT 3 R‐expressing interneurons (5‐HT 3 R‐INs) to disinhibit excitatory pyramidal neurons. The current study determined for the first time the effect of vortioxetine on the in vivo firing of putative 5‐HT 3 R‐INs whilst simultaneously recording pyramidal neuron activity using cortical slow‐wave oscillations as a readout. Extracellular single unit and local field potential recordings were made in superficial layers of the prefrontal cortex of urethane‐anaesthetised rats. 5‐HT 3 R‐INs were identified by a short‐latency excitation evoked by electrical stimulation of the dorsal raphe nucleus (DRN). Juxtacellular‐labelling found such neurons had the morphological and immunohistochemical properties of 5‐HT 3 R‐INs: basket cell or bipolar cell morphology, expression of 5‐HT 3 R‐IN markers and parvalbumin‐immunonegative. Vortioxetine inhibited the short‐latency DRN‐evoked excitation of 5‐HT 3 R‐INs and simultaneously decreased cortical slow wave oscillations, indicative of pyramidal neuron activation. Likewise, the 5‐HT 3 R antagonist ondansetron inhibited the short‐latency DRN‐evoked excitation of 5‐HT 3 R‐INs. However unlike vortioxetine, ondansetron did not decrease cortical slow‐wave oscillations, suggesting a dissociation between this effect and inhibition of 5‐HT 3 R‐INs. The 5‐HT reuptake inhibitor escitalopram had no consistent effect on any electrophysiological parameter measured. Overall, the current findings suggest that vortioxetine simultaneously inhibits (DRN‐evoked) 5‐HT 3 R‐INs 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‐HT 3 R‐mediated mechanism.