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.
Marek
G J
GJ
Department of Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven 06508, USA.
Aghajanian
G K
GK
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004338:Drug Combinations; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D009833:Olfactory Pathways / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*
D004338:Drug Combinations; D010703:Phorbol Esters; D011985:Receptors, Serotonin; C008874:phorbol-12,13-diacetate; D012701:Serotonin; D002217:Carbachol; D011493:Protein Kinase C; D009638:Norepinephrine