5-Hydroxytryptamine (5-HT) neurons in the midbrain dorsal raphe nucleus (DRN) are implicated in the drug treatment and pathophysiology of a wide variety of neuropsychiatric disorders. Accumulating evidence suggests that 5-HT6 receptors may be located and functional in the DRN; therefore, 5-HT6 receptor ligands may have potential as novel modulators of 5-HT neurotransmission. The current study investigated the effect of intravenous (i.v.) administration of the selective 5-HT6 receptor agonist, WAY-181187, and antagonist, SB-399885, on the firing of 5-HT neurons in the DRN in vivo. Extracellular recordings were made in the DRN of anesthetized rats, and single 5-HT neurons were identified on the basis of electrophysiological properties combined with juxtacellular labeling and postmortem immunohistochemical analysis. WAY-181187 (1-4 mg/kg i.v.) caused a dose-dependent increase in 5-HT neuron firing rate. In comparison, SB-399885 (0.125-1 mg/kg i.v.) caused a dose-dependent decrease in 5-HT neuron firing rate, an effect reversed by WAY-181187 (3 mg/kg i.v.). These effects of WAY-181187 and SB-399885 were observed in two separate sets of experiments. In summary, the current data show the modulation of 5-HT neuronal firing by the 5-HT6 ligands WAY-181187 and SB-399885 and are consistent with the presence of 5-HT6 receptor-mediated positive feedback control of 5-HT neurons.

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.