Abstract

The overall goal of this project is to determine molecular events that underlie cellular adaptation to alcohol with the hope of identifying novel drug targets for treatment of alcoholism. Considerable evidence implicates voltage-dependent calcium channels in alcohol consumption and dependence in animals. Prior work has focused mainly on L-type, voltage- gated calcium channels, which are inhibited by ethanol and are up- regulated by chronic ethanol exposure in vitro. Moreover, binding sites for omega-conotoxin GVIA, a specific N channel antagonist, are increased in mouse hippocampus following chronic exposure to ethanol. In PC12 cells, up-regulation of N channels by chronic ethanol exposure requires protein kinase C (PKC)epsilon. The first goal of this project is to determine if up- regulation of N-type channels by ethanol is reversible and leads to reversible changes in N channel function. Subsequent studies will investigate whether ethanol increases N channel density by increasing channel subunit mRNA or intracellular trafficking of subunit proteins by PKCepsilon-dependent mechanisms. Using a newly created PKCepsilon knockout mouse, the role of PKCepsilon in alcohol preference, tolerance, and dependence will be examined in behavioral studies of two-bottle preference, loss of righting reflex, and alcohol withdrawal seizures. Finally, the role of PKCepsilon in ethanol-induced up-regulation of N channels in vivo will be examined using these PKCepsilon knockout mice. These studies will provide specific information about the role of PKCepsilon in mediating ethanol-induced changes in functional N channels in vitro and in vivo. Important information will be obtained regarding the role of PKCepsilon in regulating alcohol preference, tolerance, and dependance in animals. These results will advance our knowledge about mechanisms underlying drinking behavior and may identify N-type channels and PKCepsilon as new targets for development of therapeutic agents to treat alcoholism.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
2R01AA008117-10A1
Application #
2842615
Study Section
Special Emphasis Panel (ZRG1-ALTX-3 (01))
Project Start
1989-12-01
Project End
2004-06-30
Budget Start
1999-09-30
Budget End
2000-06-30
Support Year
10
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608

  Publications

Newton, Philip M; Zeng, Lily; Wang, Victoria et al. (2008) A blocker of N- and T-type voltage-gated calcium channels attenuates ethanol-induced intoxication, place preference, self-administration, and reinstatement. J Neurosci 28:11712-9
Newton, P M; Messing, R O (2006) Intracellular signaling pathways that regulate behavioral responses to ethanol. Pharmacol Ther 109:227-37
Newton, Philip M; Tully, Keith; McMahon, Thomas et al. (2005) Chronic ethanol exposure induces an N-type calcium channel splice variant with altered channel kinetics. FEBS Lett 579:671-6
Song, M; Messing, R O (2005) Protein kinase C regulation of GABAA receptors. Cell Mol Life Sci 62:119-27
Olive, M Foster; McGeehan, Andrew J; Kinder, Jennifer R et al. (2005) The mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine decreases ethanol consumption via a protein kinase C epsilon-dependent mechanism. Mol Pharmacol 67:349-55
Olive, M Foster; Messing, Robert O (2004) Protein kinase C isozymes and addiction. Mol Neurobiol 29:139-54
Newton, Philip M; Orr, Christine J; Wallace, Melisa J et al. (2004) Deletion of N-type calcium channels alters ethanol reward and reduces ethanol consumption in mice. J Neurosci 24:9862-9
Choi, Doo-Sup; Messing, Robert O (2003) Animal models in the study of protein kinase C isozymes. Methods Mol Biol 233:455-73
Choi, Doo-Sup; Wang, Dan; Dadgar, Jahan et al. (2002) Conditional rescue of protein kinase C epsilon regulates ethanol preference and hypnotic sensitivity in adult mice. J Neurosci 22:9905-11
Hodge, Clyde W; Raber, Jacob; McMahon, Thomas et al. (2002) Decreased anxiety-like behavior, reduced stress hormones, and neurosteroid supersensitivity in mice lacking protein kinase Cepsilon. J Clin Invest 110:1003-10

Showing the most recent 10 out of 14 publications