Figure 1. 5-HT inhibits L6 pyramidal neurons of medial prefrontal cortex. Responses to 5-HT were probed in voltage-clamp and current-clamp by bath application of 5-HT. Representative voltage-clamp traces of the 5-HT response in L6 pyramidal neurons show that responses to 5-HT are stable and persist in the presence of synaptic blockers (A), are significantly suppressed by WAY100635 (B), and are similarly suppressed by a combination of WAY100635 and synaptic blockers (C). D, 5-HT elicits strong outward currents on L6 pyramidal neurons of mPFC (n = 28) that can be pharmacologically modulated (F(2,53) = 11.8, p < 0.0001, one-way ANOVA). Post hoc analyses show that these currents persist in the presence of synaptic blockers (q = 0.2, p > 0.05, n = 7, Dunnett’s multiple comparison test) but are significantly suppressed by WAY100635 (q = 4.6, p < 0.0001, n = 19). Responses to 5-HT were probed in current-clamp in L6 pyramidal neurons of medial prefrontal cortex with current injection to elicit steady firing (∼2–3 Hz) at baseline. Representative current-clamp traces show that responses to 5-HT are inhibitory, repeatable, and unaffected by synaptic blockers (E) and not fully blocked by WAY100635 (F) or by WAY100635 and synaptic blockers (G). H, L6 pyramidal neurons of mPFC are strongly hyperpolarized by 5-HT (n = 26). Post hoc analyses of pharmacological effects on this hyperpolarization (F(2,50) = 17, p < 0.0001, one-way ANOVA) show that this inhibition is unaffected by synaptic blockers (q = 0.8, p > 0.5, n = 6, Dunnett’s multiple comparison test) but greatly reduced by WAY100635 (q = 5.4, p < 0.0001, n = 21). I, Action potential firing was significantly affected by 5-HT (F(4,103) = 37, p < 0.0001, one-way ANOVA). Post hoc analyses reveal that baseline firing was strongly suppressed by 5-HT (q = 9, p < 0.0001, n = 17, Dunnett’s multiple comparison test) and remained suppressed by 5-HT in synaptic blockers (q = 6.1, p < 0.0001, n = 6). The suppression was not blocked by WAY100635 (q = 8.8, p < 0.0001, n = 16) and returned to baseline levels after washout of 5-HT (q = 2.3, p > 0.05, n = 36).