Alcohol abuse and alcoholism are widespread public health problems that are associated with debilitating medical, social, and psychological consequences. The abuse of alcohol is controlled by multiple effects of the drug, including its subjective and reinforcing effects and its capacity to trigger relapse. Preclinical methods have been developed to assess the contribution of these controlling factors and their neurobiological underpinnings, and to provide empirically-based models for evaluating potential treatment strategies. The purpose of this renewal application is to investigate the role of a2/3GABAA and a5GABAA receptor mechanisms in nonhuman primate models of the abuse-related effects of alcohol. We will systematically investigate the contribution of a2/3GABAA receptor mechanisms (Specific Aim 1) to the behavioral effects of alcohol by determining how receptor selective agonists and antagonists modulate: 1) the discriminative stimulus effects of alcohol in rhesus monkeys trained to discriminate intragastrically-administered alcohol from vehicle, 2) oral self-administration of alcohol in rhesus monkeys, and 3) reinstatement of alcohol seeking in rhesus monkeys whose oral self-administration has been extinguished and subsequently reinstated by alcohol priming. Understanding the neuropharmacological mechanisms underlying the addictive effects of alcohol is an important initial step in the development of candidate pharmacotherapies for the treatment of alcohol abuse and dependence. Additionally, we will continue to evaluate novel a5GABAA receptor inverse agonists with different chemical structures and potentially more suitable behavioral profiles in these same behavioral models (Specific Aim 2). Results from these studies should support the notion of the a5GABAA receptor as a relevant target for the pharmacological management of alcohol use disorders. The degree to which the effects of a2/3GABAA and a5GABAA receptor ligands selectively modify alcohol-controlled behavior (Specific Aim 3) will be evaluated in rhesus monkeys that self-administer a sucrose solution instead of alcohol and in concurrent observational studies of the effects these ligands, alone or combined with alcohol, on unconditioned motor behavior. The ability of selected a2/3GABAA and a5GABAA ligands to blunt the discriminative stimulus effects of alcohol, reduce alcohol self-administration and attenuate priming-induced reinstatement of alcohol seeking at doses that do not produce a generalized disruption of behavior or debilitating side effects may be predictive of potential therapeutic utility. Integration of results from these three specific aims will provide needed information about specific GABAA mechanisms that may underlie the addictive effects of alcohol and will aid identification of receptor targets for the pharmacological management of alcohol abuse and relapse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
7R01AA016179-08
Application #
8726888
Study Section
Special Emphasis Panel ()
Program Officer
Egli, Mark
Project Start
2006-06-15
Project End
2017-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
Fiscal Year
2013
Total Cost
$264,225
Indirect Cost
$90,963
Name
University of Mississippi Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Sawyer, Eileen K; Moran, Casey; Sirbu, Madelynn H et al. (2014) Little evidence of a role for the *1GABAA subunit-containing receptor in a rhesus monkey model of alcohol drinking. Alcohol Clin Exp Res 38:1108-17
Shinday, Nina M; Sawyer, Eileen K; Fischer, Bradford D et al. (2013) Reinforcing effects of compounds lacking intrinsic efficacy at *1 subunit-containing GABAA receptor subtypes in midazolam- but not cocaine-experienced rhesus monkeys. Neuropsychopharmacology 38:1006-14
Ishikawa, Masago; Otaka, Mami; Neumann, Peter A et al. (2013) Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens. J Physiol 591:4827-41
Fischer, Bradford D; Atack, John R; Platt, Donna M et al. (2011) Contribution of GABA(A) receptors containing ýý3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys. Psychopharmacology (Berl) 215:311-9
Platt, Donna M; Bano, Kristen M (2011) Opioid receptors and the discriminative stimulus effects of ethanol in squirrel monkeys: Mu and delta opioid receptor mechanisms. Eur J Pharmacol 650:233-9
Namjoshi, Ojas A; Gryboski, Angelica; Fonseca, German O et al. (2011) Development of a two-step route to 3-PBC and ýýCCt, two agents active against alcohol self-administration in rodent and primate models. J Org Chem 76:4721-7
Vallender, Eric J; Ruedi-Bettschen, Daniela; Miller, Gregory M et al. (2010) A pharmacogenetic model of naltrexone-induced attenuation of alcohol consumption in rhesus monkeys. Drug Alcohol Depend 109:252-6
Licata, Stephanie C; Platt, Donna M; Rüedi-Bettschen, Daniela et al. (2010) Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): role of GABA(A) receptor subtypes. Neuropharmacology 58:357-64
Licata, Stephanie C; Platt, Donna M; Cook, James M et al. (2009) Contribution of alpha1 subunit-containing gamma-aminobutyric acidA (GABAA) receptors to motor-impairing effects of benzodiazepines in squirrel monkeys. Psychopharmacology (Berl) 203:539-46