Ethanol produces internal stimulus effects that are reinforcing and that maintain either social or pathological drinking in a large number of individuals. The drug discrimination procedure is a particularly useful technique to characterize the receptor mechanisms that mediate the internal stimulus effects of drugs. The overall goal of the proposed research is to assess the contribution of specific ligand-gated ion channels (GABAA and NMDA) in mediating the mixed discriminative stimulus effects of ethanol. Thus, the aims of the present proposal are to continue the development of a model to characterize ethanol's direct and concurrent activity at a number of receptor systems and explore behavioral correlates of some newly identified cellular mechanisms of ethanol's activity. These five new Specific Aims are: l. To investigate the discriminative stimulus effects of ethanol mediated by NMDA and GABAA receptor systems as a function of ethanol training dose. 2. To investigate the optimal ligand to represent the modulatory effects of ethanol at the GABAA (or NMDA) receptor in characterizing receptor interactions. 3. To determine if discriminative stimulus effects that are unique to ethanol are due, in part, to an interaction between ethanol-sensitive GABAA and NMDA receptor systems. 4. To determine whether the ethanol-like effects of the 5-HTIB agonists are secondary to ethanol's effects of GABAA receptors. 5. To assess the potentiation of ethanol's activity at a ligand-gated ion channel by activating metabotropic receptors with drug discrimination. The immediate significance of the proposed studies will be to extend information on ethanol as a mixed stimulus in the CNS, composed of, but not limited to, actions at specific sites on ligand-gated ion channels. These findings will suggest variables that determine the effectiveness of pharmacological agents to block ethanol's stimulus effects, and may suggest the appropriate receptor system(s) to target.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA009346-09
Application #
6168262
Study Section
Special Emphasis Panel (ZRG4-ALTX-3 (01))
Program Officer
Egli, Mark
Project Start
1992-07-01
Project End
2002-06-30
Budget Start
2000-07-01
Budget End
2001-06-30
Support Year
9
Fiscal Year
2000
Total Cost
$172,264
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
Buck, Kari J; Reilly, Matthew T; Rogers, Laura M et al. (2004) Serotonin 5-HT2 receptors and alcohol: reward, withdrawal and discrimination. Alcohol Clin Exp Res 28:211-6
Quertemont, E; Grant, K A (2004) Discriminative stimulus effects of ethanol: lack of interaction with taurine. Behav Pharmacol 15:495-501
Green-Jordan, K; Grant, K A (2000) Modulation of the ethanol-like discriminative stimulus effects of diazepam and phencyclidine by L-type voltage-gated calcium-channel ligands in rats. Psychopharmacology (Berl) 149:84-92
Green, K L; Grant, K A (1999) Effects of L-type voltage-sensitive calcium channel modulators on the discriminative stimulus effects of ethanol in rats. Alcohol Clin Exp Res 23:806-14
Bowen, C A; Purdy, R H; Grant, K A (1999) Ethanol-like discriminative stimulus effects of endogenous neuroactive steroids: effect of ethanol training dose and dosing procedure. J Pharmacol Exp Ther 289:405-11
Bowen, C A; Grant, K A (1999) Increased specificity of ethanol's discriminative stimulus effects in an ethanol-pentobarbital-water discrimination in rats. Drug Alcohol Depend 55:13-24
Grant, K A (1999) Strategies for understanding the pharmacological effects of ethanol with drug discrimination procedures. Pharmacol Biochem Behav 64:261-7
Bowen, C A; Purdy, R H; Grant, K A (1999) An investigation of endogenous neuroactive steroid-induced modulation of ethanol's discriminative stimulus effects. Behav Pharmacol 10:297-311
Bowen, C A; Grant, K A (1998) Pharmacological analysis of the heterogeneous discriminative stimulus effects of ethanol in rats using a three-choice ethanol-dizocilpine-water discrimination. Psychopharmacology (Berl) 139:86-94
Szeliga, K T; Grant, K A (1998) Analysis of the 5-HT2 receptor ligands dimethoxy-4-indophenyl-2-aminopropane and ketanserin in ethanol discriminations. Alcohol Clin Exp Res 22:646-51

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