There is increasing evidence that GABAA-benzodiazepine (BDZ) receptors are involved in the regulation of EtOH-self- administration. The goal of this proposal is to identify specific neurobiological substrates of GABAA-BDZ neurotransmission which mediate EtOH reinforcement. To accomplish this goal, the selectively bred high alcohol drinking (HAD) 1 and 2 rat lines will be used. The main hypothesis to be tested is that GABAA-BDZ neuroanatomical circuits in two extended amygdala loci [e.g., central nucleus of the amygdala, bed nucleus of the stria terminalis], mediate in part, activation of underlying neuroanatomical substrates contributing to the reinforcing properties of EtOH. First, dose-effect and time course studies will examine the capacity of site-specific microinjections of high affinity BDZ inverse agonists, a BDZ antagonist and the GABAA antagonist SR 95531 in the central nucleus of the amygdala and bed nucleus of the stria terminalis to attenuate EtOH intake using scheduled controlled responding (i.e., operant methodology). It is hypothesized that inverse agonists and antagonists with similar binding affinity should be equally effective as EtOH antagonists. Effective antagonists (i.e., inverse agonists) of EtOH-maintained responding should be antagonized by competitive BDZ antagonist, since their suppression should be mediated by a direct action at the BDZ component of the GABAA complex. Second, to systematically evaluate the selectivity of the agents to suppress EtOH-motivated responding, a 4-stage behavioral analysis will be employed. It is hypothesized that agents (e.g., inverse agonists, BDZ antagonist, SR 95531) which specifically affect the reinforcing aspects of EtOH should not alter responding of alternative reinforcers with similar reinforcing efficacy (i.e., saccharin), or similar post-ingestional caloric properties (i.e., sucrose). Finally, it is hypothesized that interactions at GABAA-BDZ sites may modulate the function of monoaminergic neurons sustaining EtOH-seeking behaviors. These studies should contribute to a scientific understanding of the role of GABAA-BDZ receptor complex plays in regulating EtOH seeking behavior.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Witt, Ellen
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Indiana University-Purdue University at Indianapolis
Schools of Arts and Sciences
United States
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Yang, Andrew Rong Song Tzeng; Yi, Heon Soo; Mamczarz, Jacek et al. (2009) Deficits in substance P mRNA levels in the CeA are inversely associated with alcohol-motivated responding. Synapse 63:972-81
June, Harry L; Tzeng Yang, Andrew Rong Song; Bryant, Joseph L et al. (2009) Vitamin A deficiency and behavioral and motor deficits in the human immunodeficiency virus type 1 transgenic rat. J Neurovirol 15:380-9
June Sr, Harry L; Foster, Katrina L; Eiler 2nd, William J A et al. (2007) Dopamine and benzodiazepine-dependent mechanisms regulate the EtOH-enhanced locomotor stimulation in the GABAA alpha1 subunit null mutant mice. Neuropsychopharmacology 32:137-52
Eiler 2nd, William J A; June, Harry L (2007) Blockade of GABA(A) receptors within the extended amygdala attenuates D(2) regulation of alcohol-motivated behaviors in the ventral tegmental area of alcohol-preferring (P) rats. Neuropharmacology 52:1570-9
Eiler 2nd, William J A; Hardy 3rd, Lathen; Goergen, Josuha et al. (2007) Responding for brain stimulation reward in the bed nucleus of the stria terminalis in alcohol-preferring rats following alcohol and amphetamine pretreatments. Synapse 61:912-24
Eiler 2nd, William J A; Woods 2nd, James E; Masters, Jacob et al. (2005) Brain stimulation reward performance and sucrose maintained behaviors in alcohol-preferring and -nonpreferring rats. Alcohol Clin Exp Res 29:571-83
Cook, Jason B; Foster, Katrina L; Eiler 2nd, William J A et al. (2005) Selective GABAA alpha5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol. Alcohol Clin Exp Res 29:1390-401
June, Harry L; Cummings, Rancia; Eiler 2nd, William J A et al. (2004) Central opioid receptors differentially regulate the nalmefene-induced suppression of ethanol- and saccharin-reinforced behaviors in alcohol-preferring (P) rats. Neuropsychopharmacology 29:285-99
McKay, Peter F; Foster, Katrina L; Mason, Dynesha et al. (2004) A high affinity ligand for GABAA-receptor containing alpha5 subunit antagonizes ethanol's neurobehavioral effects in Long-Evans rats. Psychopharmacology (Berl) 172:455-62
Woods 2nd, James E; McKay, Peter F; Masters, Jacob et al. (2003) Differential responding for brain stimulation reward and sucrose in high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) rats. Alcohol Clin Exp Res 27:926-36

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