Recent evidence suggests that the epsilon isoform of protein kinase C (PKCepsilon) plays a critical role in ethanol-seeking behavior. We recently demonstrated that mice lacking PKCepsilon and consume 50-75% less ethanol than their wildtype counterparts in two separate self-administration paradigms. We also demonstrated that PKCepsilon null mutant mice demonstrate reduced ethanol intake following deprivation (a model of relapse), reduced ethanol withdrawal severity, and a lack of ethanol-stimulated mesolimbic dopamine release. These data suggest that selective pharmacological inhibition of PKCepsilon activity may be a novel therapeutic avenue for the treatment of various aspects of alcoholism. However, given the high degree of structural homology between PKC isoforms, to date there are no specific CNS-penetrant pharmacological compounds that selectively inhibit PKC activity. An alternative approach to directly inhibiting PKCepsilon activity is to pharmacologically modulate a specific neurotransmitter receptor system that is directly coupled to PKCepsilon. Our preliminary data show that the type 5 metabotropic glutamate receptor (mGluR5) may be functionally linked to PKCepsilon activity. We show that the selective mGluR5 antagonist MPEP reduces ethanol self-administration and enhances ethanol-stimulated locomotor activity in a PKCepsilon-dependent manner. We also show that PKCepsilon and mGluR5 immunoreactivity are highly co-localized in brain regions known to be involved in ethanol consumption and reinforcement. Finally, MPEP reduces the rewarding effects of ethanol as measured by the conditioned place preference paradigms. Taken together, these data indicate that the mGluR5 receptor may be functionally coupled to PKCepsilon, and that selective mGluR5 antagonists may be useful in treating excessive alcohol consumption, relapse following detoxification, and withdrawal symptom severity. The following Specific Aims describe preclinical experiments designed to investigate the functional coupling between mGluR5 and PKCepsilon, and to evaluate the ability of mGluR5 antagonists to reduce ethanol-stimulated mesolimbic dopamine release, relapse to drinking following deprivation, and withdrawal severity. The first specific aim will be to biochemically characterize the functional coupling between the mGluR5 receptor and PKCepsilon activity. The second specific aim will determine if mGluR5 antagonists inhibit ethanol-stimulated mesolimbic dopamine release, a phenomenon thought to contribute to the reinforcing properties of ethanol. The third specific aim will determine if mGluR5 antagonists reduce relapse to ethanol self-administration following deprivation in both wildtype and PKCepsilon null mutant mice. Finally, the fourth specific aim will determine if mGluR5 antagonism attenuates ethanol withdrawal severity in both wildtype and PKCepsilon null mutant mice. Together, these proposed preclinical studies will attempt to delineate a novel pharmacological target that may be used to treat various aspects of alcohol abuse and alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
1R01AA013852-01
Application #
6555539
Study Section
Special Emphasis Panel (ZAA1-CC (15))
Program Officer
Silverman, Peter
Project Start
2003-02-01
Project End
2008-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
1
Fiscal Year
2003
Total Cost
$283,850
Indirect Cost
Name
Ernest Gallo Clinic and Research Center
Department
Type
DUNS #
173995366
City
Emeryville
State
CA
Country
United States
Zip Code
94608
Schwendt, Marek; Olive, M Foster (2017) Protein kinase C? activity regulates mGluR5 surface expression in the rat nucleus accumbens. J Neurosci Res 95:1079-1090
Steffensen, Scott C; Shin, Samuel I; Nelson, Ashley C et al. (2017) ?6 subunit-containing nicotinic receptors mediate low-dose ethanol effects on ventral tegmental area neurons and ethanol reward. Addict Biol :
Olive, Michael F (2015) Neurokinin-1 (NK?) receptor antagonists as possible therapeutics for psychostimulant use disorders. CNS Neurol Disord Drug Targets 14:700-6
LaCrosse, Amber L; Taylor, Sara B; Nemirovsky, Natali E et al. (2015) mGluR5 Positive and Negative Allosteric Modulators Differentially Affect Dendritic Spine Density and Morphology in the Prefrontal Cortex. CNS Neurol Disord Drug Targets 14:476-85
Kufahl, Peter R; Watterson, Lucas R; Olive, M Foster (2014) The development of acamprosate as a treatment against alcohol relapse. Expert Opin Drug Discov 9:1355-69
Gass, Justin T; Trantham-Davidson, Heather; Kassab, Amanda S et al. (2014) Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex. J Neurosci 34:7562-74
Carrara-Nascimento, Priscila F; Lopez, Marcelo F; Becker, Howard C et al. (2013) Similar ethanol drinking in adolescent and adult C57BL/6J mice after chronic ethanol exposure and withdrawal. Alcohol Clin Exp Res 37:961-8
Yahn, Stephanie L; Watterson, Lucas R; Olive, M Foster (2013) Safety and efficacy of acamprosate for the treatment of alcohol dependence. Subst Abuse 6:1-12
Cleva, Richard M; Olive, M Foster (2012) mGlu receptors and drug addiction. Wiley Interdiscip Rev Membr Transp Signal 1:281-295
Olive, M Foster (2012) Ethanol, glutamate, and the ventral tegmental area--a commentary on: Ding, Engleman, Rodd, and McBride, ""ethanol increases glutamate neurotransmission in the posterior ventral tegmental area of female wistar rats"". Alcohol Clin Exp Res 36:970-1

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