Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cgamma.
Protein kinase Cgamma (PKCgamma) null mutant mice demonstrate increased behavioral impulsivity and ethanol consumption. Pharmacological studies have shown that 5-HT(2A/C) receptors modulate impulsivity and ethanol consumption in rodents and that PKC can regulate 5-HT(2A/C) receptors. To determine whether PKCgamma plays a selective role in 5-HT(2A/C) receptor regulation, biochemical and behavioral experiments were performed in PKCgamma mutant and wild-type mice. DOI-stimulated phosphoinositol hydrolysis and [(125)I]-DOI saturation binding in the PFC, and quantitative autoradiography of [(125)I]-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-HT(2A/C) receptor function in the PFC, but not increased receptor number or affinity suggesting that PKCgamma regulates receptor function but not receptor number. These data support a role for 5-HT(2A/C) receptors in the PFC in mediating some of the behavioral differences observed between PKCgamma mutant and wild-type mice.
Bowers
Barbara J
BJ
Institute for Behavioral Genetics, University of Colorado, Boulder, CO 80309, USA. bbowers@colorado.edu
Miyamoto-Ditmon
Jill
J
Wehner
Jeanne M
JM
D000428:Alcohol Drinking; D000662:Amphetamines / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011493:Protein Kinase C / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D000662:Amphetamines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D017366:Serotonin Receptor Agonists; C087857:protein kinase C gamma; D011493:Protein Kinase C; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine