Abstract

The central nervous system (CNS) mechanisms that determine alcohol's addictive properties are only partly understood. Numerous studies, however, have reported that ethanol modulates the function of ligand- gated ion channels in the brain, leading to alterations in behavior. For example, gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors have been associated with the intoxicating and rewarding properties of ethanol. Interfering with these neuro- transmitter systems shows promise as a potential therapeutic strategy for treating alcohol abuse and alcoholism. All drugs of abuse share the common attribute that they produce subjective stimulus effects in humans. These stimulus properties of drugs are important determinants of abuse liability because drugs that do not produce stimulus effects are not abused. Drug discrimination procedures model these stimulus effects in animals and provide a method of understanding the neurochemical systems that mediate the subjective effects of alcohol. The studies in this project combine site-specific brain microinjection techniques with drug discrimination behavioral techniques to elucidate the transmitter systems, and brain regions, that mediate the subjective effects of alcohol.
Four specific aims are proposed to test the general hypothesis that alcohol's subjective stimulus effects are mediated by GABAA and glutamate receptors in limbic brain regions, which are known to be involved in addiction. The studies of Aims 1 and 2 will determine which binding sites on GABA,, and glutamate (i.e., including NMDA) receptors, located in limbic brain regions, mediate the discriminative stimulus effects of low and high doses of ethanol.
Aim 3 will examine interactions among these receptor systems. The experiments of Aim 4 will examine the influence of limbic GABAA and NMDA circuits involving the important brain region of the nucleus accumbens. The long range goal of these studies is to determine the specific brain mechanisms that mediate the subjective stimulus effects of alcohol with the hope of identifying novel targets for drug therapy in alcohol abuse and alcoholism.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009981-07
Application #
6371355
Study Section
Special Emphasis Panel (ZRG1-ALTX-3 (01))
Program Officer
Egli, Mark
Project Start
1997-03-01
Project End
2001-06-30
Budget Start
2001-05-01
Budget End
2001-06-30
Support Year
7
Fiscal Year
2001
Total Cost
$1
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

Besheer, Joyce; Hodge, Clyde W (2005) Pharmacological and anatomical evidence for an interaction between mGluR5- and GABA(A) alpha1-containing receptors in the discriminative stimulus effects of ethanol. Neuropsychopharmacology 30:747-57
Schroeder, Jason P; Overstreet, David H; Hodge, Clyde W (2005) The neuropeptide-Y Y5 receptor antagonist L-152,804 decreases alcohol self-administration in inbred alcohol-preferring (iP) rats. Alcohol 36:179-86
Besheer, Joyce; Lepoutre, Veronique; Hodge, Clyde W (2004) GABA(B) receptor agonists reduce operant ethanol self-administration and enhance ethanol sedation in C57BL/6J mice. Psychopharmacology (Berl) 174:358-66
Hodge, Clyde W; Kelley, Stephen P; Bratt, Alison M et al. (2004) 5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking. Neuropsychopharmacology 29:1807-13
Camarini, Rosana; Hodge, Clyde W (2004) Ethanol preexposure increases ethanol self-administration in C57BL/6J and DBA/2J mice. Pharmacol Biochem Behav 79:623-32
Besheer, Joyce; Cox, Amy A; Hodge, Clyde W (2003) Coregulation of ethanol discrimination by the nucleus accumbens and amygdala. Alcohol Clin Exp Res 27:450-6
Schroeder, Jason P; Iller, Kimberly A; Hodge, Clyde W (2003) Neuropeptide-Y Y5 receptors modulate the onset and maintenance of operant ethanol self-administration. Alcohol Clin Exp Res 27:1912-20
Kelley, Stephen P; Hodge, Clyde W (2003) The 5-HT3 antagonist Y-25130 blocks cocaine-induced lowering of ICSS reward thresholds in the rat. Pharmacol Biochem Behav 74:297-302
Schroeder, Jason P; Olive, Foster; Koenig, Heather et al. (2003) Intra-amygdala infusion of the NPY Y1 receptor antagonist BIBP 3226 attenuates operant ethanol self-administration. Alcohol Clin Exp Res 27:1884-91
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

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