Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cγ

Abstract: Protein kinase Cγ (PKCγ) null mutant mice demonstrate increased behavioral impulsivity and ethanol consumption. Pharmacological studies have shown that 5-HT2A/C receptors modulate impulsivity and ethanol consumption in rodents and that PKC can regulate 5-HT2A/C receptors. To determine whether PKCγ plays a selective role in 5-HT2A/C receptor regulation, biochemical and behavioral experiments were performed in PKCγ mutant and wild-type mice. DOI-stimulated phosphoinositol hydrolysis and [125I]-DOI saturation binding in the PFC, and quantitative autoradiography of [125I]-DOI binding sites in 15 brain regions were analyzed. DOI-induced head twitch responses (HTR) were measured in naive mice after an acute 2.5 mg/kg injection of DOI. Results indicated that DOI-induced HTR was significantly greater in mutant mice compared to wild-type mice. Results of the phosphoinositol hydrolysis, membrane binding, and autoradiography experiments indicated that in mutant mice, increased HTR was associated with increased 5-HT2A/C receptor function in the PFC, but not increased receptor number or affinity suggesting that PKCγ regulates receptor function but not receptor number. These data support a role for 5-HT2A/C receptors in the PFC in mediating some of the behavioral differences observed between PKCγ mutant and wild-type mice. [Copyright &y& Elsevier]