The overall goal of the proposed research is to characterize the pharmacological basis of the subjective effects of alcohol in a non-human primate model. This model uses a drug discrimination procedures to define receptor mechanisms that mediate the interoceptive (or subjective) stimulus effects of ethanol. Studies in the preceding period of funding have suggested that positive modulation of GABAA receptors appears to produce the most robust ethanol-like stimulus across training dose and gender. Of the GABAA ligands, the endogenous neurosteroids offer a unique opportunity to study mechanisms of physiological states that alter sensitivity to the subjective effects of ethanol. The proposed studies will use neurosteroids to define GABAA, subtypes of receptors that mediate the discriminative stimulus effects of ethanol; test novel steroid analogs to produce discriminative stimulus effects though NMDA inhibition; and use menstrual cycle phase to test hypotheses concerning alterations in GABAA receptor subtypes leading to changes in sensitivity to ethanol. Perhaps functionally linked to the GABAA receptor system are specific serotonin receptor subtypes that produce opposite effects on sensitivity to ethanol's discriminative stimulus effects. The proposed studies will further characterize these interactions. Overall, the results from the proposed studies should advance our understanding of endogenous mechanisms that alter sensitivity to the subjective effects of ethanol in a non-human primate species.
The specific aims are the research are: 1) To characterize the neurosteroid modulation of GABAA receptors and the discriminative stimulus effects of ethanol. 2) To characterize the neurosteroid modulation of NMDA receptors and the discriminative stimulus effects of ethanol. 3) To characterize the influence of menstrual cycle phase on neurosteroid modulation of the discriminative stimulus effects of ethanol. 4) To characterize the 5-HT1D and 5-HT2C modulation of the discriminative stimulus effects of ethanol.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA010009-09
Application #
6629585
Study Section
Alcohol and Toxicology Subcommittee 4 (ALTX)
Program Officer
Silverman, Peter
Project Start
1994-04-01
Project End
2005-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
9
Fiscal Year
2003
Total Cost
$235,836
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Physiology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Helms, Christa M; Rogers, Laura S M; Grant, Kathleen A (2009) Antagonism of the ethanol-like discriminative stimulus effects of ethanol, pentobarbital, and midazolam in cynomolgus monkeys reveals involvement of specific GABA(A) receptor subtypes. J Pharmacol Exp Ther 331:142-52
Helms, Christa M; Rogers, Laura S M; Waters, Courtney A et al. (2008) Zolpidem generalization and antagonism in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol. Alcohol Clin Exp Res 32:1197-206
Helms, Christa M; Rogers, Laura S M; Grant, Kathleen A (2008) Gamma-hydroxybutyric acid in male and female cynomolgus monkeys trained to discriminate 1.0 or 2.0 g/kg ethanol. Behav Pharmacol 19:317-24
Grant, Kathleen A; Helms, Christa M; Rogers, Laura S M et al. (2008) Neuroactive steroid stereospecificity of ethanol-like discriminative stimulus effects in monkeys. J Pharmacol Exp Ther 326:354-61
Porcu, P; Grant, K A (2004) Discriminative stimulus effects of ethanol in rats using a three-choice ethanol-midazolam-water discrimination. Behav Pharmacol 15:555-67
Vivian, Jeffrey A; Waters, Courtney A; Szeliga, Kendall T et al. (2002) Characterization of the discriminative stimulus effects of N-methyl- D-aspartate ligands under different ethanol training conditions in the cynomolgus monkey ( Macaca fascicularis). Psychopharmacology (Berl) 162:273-81
Grant, K A; Waters, C A; Green-Jordan, K et al. (2000) Characterization of the discriminative stimulus effects of GABA(A) receptor ligands in Macaca fascicularis monkeys under different ethanol training conditions. Psychopharmacology (Berl) 152:181-8
Grant, K A (1999) Strategies for understanding the pharmacological effects of ethanol with drug discrimination procedures. Pharmacol Biochem Behav 64:261-7
Green, K L; Szeliga, K T; Bowen, C A et al. (1999) Comparison of ethanol metabolism in male and female cynomolgus macaques (Macaca fascicularis). Alcohol Clin Exp Res 23:611-6
Green, K L; Azarov, A V; Szeliga, K T et al. (1999) The influence of menstrual cycle phase on sensitivity to ethanol-like discriminative stimulus effects of GABA(A)-positive modulators. Pharmacol Biochem Behav 64:379-83

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