Protein kinase C inhibitors enhance the 5-HT2A receptor-mediated excitatory effects of serotonin on interneurons in rat piriform cortex.

Previously it has been shown that excitatory effects of 5-hydroxytryptamine (5-HT) upon interneurons in the rat piriform cortex are mediated by 5-HT2A receptors. This receptor is linked to phosphoinositide turnover, and one consequence of stimulating this receptor is the activation of protein kinase C (PKC). In the present study, the effect of PKC inhibitors on the 5-HT excitation of piriform cortical interneurons was examined by extracellular recording in a rat brain slice preparation. Bath application of the selective PKC inhibitors, bisindolymalemide and chelerythrine, and the nonselective protein kinase inhibitor, H-7, all enhanced the excitatory effects of 5-HT. Two other nonselective protein kinase inhibitors, H-8 and HA 1004, which are 2.5-fold and 6.7-fold less potent than H-7 at inhibiting PKC, produced a slight or no enhancement, respectively, of the excitatory effect of 5-HT. Bisindolylmalemide, chelerytrine, and H-7 did not enhance the excitatory effects of norepinephrine or carbachol on the same interneurons. The PKC activator phorbol 12, 13-diacetate (PDA) decreased the excitatory effect of 5-HT; this decrease was rapidly reversed by H-7. As inhibitors of PKC selectively enhanced rather than blocked the excitation by 5-HT mediated by 5-HT2A receptors, we conclude that activation of PKC does not mediate the excitation by 5-HT of piriform cortical interneurons. Instead, we propose that PKC may have a negative feedback role in modulating the excitation by 5-HT of piriform cortical interneurons.