In vivo electrophysiological study of the targeting of 5-HT3 receptor-expressing cortical interneurons by the multimodal antidepressant, vortioxetine

Abstract

The antidepressant vortioxetine has high affinity for the ionotropic 5-HT3 receptor (5-HT3R) 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-HT3R-expressing interneurons (5-HT3R-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-HT3R-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-HT3R-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-HT3R-INs; basket cell or bipolar cell morphology, expression of 5-HT3R-IN markers, and parvalbumin-immunonegative. Vortioxetine inhibited the short-latency DRN-evoked excitation of 5-HT3R-INs and simultaneously decreased cortical slow wave oscillations, indicative of pyramidal neuron activation. Likewise, the 5-HT3R antagonist ondansetron inhibited the short-latency DRN-evoked excitation of 5-HT3R-INs. However unlike vortioxetine, ondansetron did not decrease cortical slow-wave oscillations suggesting a dissociation between this effect and inhibition of 5-HT3R-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-HT3R-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-HT3R-mediated mechanism.