Serotonergic regulation of calcium‐activated potassium currents in rodent prefrontal cortex

In spite of a growing understanding of the actions of 5‐hydroxytryptamine (5‐HT) in the prefrontal cortex, the specific cellular mechanism used by 5‐HT in this region remains poorly understood. Previous studies have shown that 5‐HT inhibits the afterhyperpolarization that follows a burst of spikes in pyramidal neurons. In the present study, we have used whole cell recordings in rat and mouse brain slices to re‐examine this phenomenon with special emphasis on identifying the 5‐HT receptor subtypes mediating this effect. Layer V pyramidal neurons display complex afterhyperpolarizations that are mediated predominantly by calcium‐activated potassium channels and involve two distinct currents known as medium afterhyperpolarizating current and slow afterhyperpolarizating current (I sAHP ). Administration of 5‐HT reduced the current underlying these afterhyperpolarizations by selectively inhibiting I sAHP . Pharmacological analysis of this response indicates that the main receptor responsible for this inhibition belongs to the 5‐HT 2A subtype. Thus, α‐methyl‐5‐HT and 2,5‐dimethoxy‐4‐bromoamphetamine (DOB) mimic the effect of 5‐HT and the effect of these agonists is blocked by MDL 100 907. Similarly, administration of α‐methyl‐5‐HT is without effect in slices derived from 5‐HT 2A receptor knockout mice. However, 5‐HT 2A receptor blockade only partially suppressed the ability of 5‐HT to inhibit I sAHP . This suggests the involvement of at least one more receptor subtype in this response. Consistent with this idea, administration of 5‐carboxyamido‐tryptamine, an agonist exhibiting no detectable affinity for 5‐HT 2A receptors, was also capable of suppressing I sAHP . These results identify 5‐HT 2A receptors as being primarily involved in mediating the 5‐HT‐induced inhibition of I sAHP in prefrontal cortex, while also recognizing a contribution by an additional 5‐HT receptor subtype.