A genetic relationship between behavioral disinhibition and alcoholism has been reported in recent studies of the etiology of alcoholism, suggesting that a shared neurochemical pathway regulates these behaviors. Disregulation of the serotonergic neurotransmitter system has been implicated as one factor in several behaviors associated with alcoholism, including behavioral disinhibition, anxiety, and high levels of alcohol consumption. This may be the result of pleiotropic regulation by one or more genes that impact the diverse family of serotonergic receptors. The identification of gene(s) underlying this shared regulation is largely unknown. We have previously demonstrated that mice lacking the neural specific y isotype of PKC demonstrate both increased impulsivity and increased ethanol consumption as well as alterations in endogenous behavioral anxiety, indicating that PKCgamma is one mediator of these behaviors Preliminary data from behavioral pharmacological investigations of serotonergic activity in PKCgamma mutant and wild-type control mice provide evidence that 5-HT2Nc and 5-HT1A receptor systems are disrupted in mutant mice. Because PKC has been shown to regulate 5-HT2A/C and 5-HT1A receptor function, the goal of the proposed studies to determine if PKCgamma, plays a specific role in regulating these receptors by investigating serotonin-mediated behaviors and 5 # HT 2A/C and 5-HT1A receptor function in PKCgamma null mutant and wild-type littermate control mice.
In specific aim # 1 5-HT2A/C agonists and antagonists will be administered to mutant and wild-type mice prior to impulsivity training or ethanol consumption to determine the association of PKCy and the 5-HT2 receptor system in regulating these behaviors.
In specific aim # 2, 5-HT2A and 5-HT2c receptors will be compared in brain tissue from naive and drug-treated mutant and wild-type mice using receptor autoradioraphy and agonist-stimulated phosphoinositide hydrolysis.
In specific aim #3 5-HT1A-mediated effects on anxiety and 5-HT1A receptor number and affinity, measured using receptor autoradiography, will be compared between mutant and wild-type mice. The results of these studies will help to elucidate the specific role of PKCgamma, in complex behaviors associated with alcohol dependence.
| Bowers, Barbara J; Miyamoto-Ditmon, Jill; Wehner, Jeanne M (2006) Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cgamma. Pharmacol Biochem Behav 85:441-7 |
| Bowers, Barbara J; Radcliffe, Richard A; Smith, Amy M et al. (2006) Microarray analysis identifies cerebellar genes sensitive to chronic ethanol treatment in PKCgamma mice. Alcohol 40:19-33 |
