Ethanol (alcohol) dependence is a chronic relapsing behavioral/brain disorder characterized by an inability to self-regulate alcohol intake. Neuroadaptation (i.e., changes in gene expression) within brain regions that mediate ethanol's reinforcing properties may be associated with loss of control over ethanol intake, or binge drinking. We will investigate the GABAergic systems of the anterior and posterior ventral tegmental area (VTA), nucleus accumbens (NAcc) shell, and medial prefrontal cortex (mPFC). Evidence suggests that the GABAergic systems in each of these structures has at least some role in the modulation of ethanol self-administration, but the role of these structures in the modulation of voluntary binge-like ethanol intake has not been examined. The goals of the current proposal are to 1) investigate the role of GABAergic receptor systems in the anterior and posterior VTA, NAcc shell, and mPFC in the modulation of binge-like ethanol intake using a recently developed limited access mouse model, and to 2) ascertain whether GABAA subunit, GABAB subtype, or other GABA-associated gene expression in the above brain structures is altered by daily binge-like ethanol intake using the same mouse model.
In aims 1 and 2, mice will receive anterior or posterior intra-VTA, -NAcc shell, or -mPFC microinjections of zolpidem or 4,5,6,7-tetrahydroisoxazolo-[5,4- c]pyridin-3-ol (THIP), known to target synaptic and extrasynaptic GABAA receptors respectively, or baclofen, an agonist at GABAB receptors, immediately prior to assessment of binge-like ethanol intake. We predict that microinjection of these drugs will reduce the behavior in a brain region specific manner.
In aim 3, binge-like ethanol intake-associated changes in GABA-related mRNA expression will be examined in the anterior and posterior VTA, NAcc shell, and mPFC using real-time polymerase chain reaction (PCR) and Western blot. We expect that binge-like ethanol intake will alter the expression of certain GABAA subunits, GABAB subtypes, and other GABA-associated transcripts in these structures. The proposed work will contribute to our general knowledge concerning the involvement of GABAergic circuits in the VTA, NAcc, and mPFC in the modulation of binge-like ethanol intake. We hope it will advance our understanding of the neurobiological factors associated with alcohol abuse and dependence in humans and ultimately lead to the development of better pharmacological tools in the treatment of alcoholism.

Public Health Relevance

The proposed work will contribute to our general knowledge concerning the involvement of GABA circuits in the ventral tegmental area, nucleus accumbens, and prefrontal cortex in the maintenance of binge-like ethanol intake. It will advance our understanding of the neurobiological factors associated with the transition from casual alcohol use to alcohol abuse and dependence in humans, and may ultimately lead to better pharmacological treatment strategies for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA016789-05
Application #
8206863
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Liu, Qi-Ying
Project Start
2009-01-01
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$391,497
Indirect Cost
$132,904
Name
Indiana University-Purdue University at Indianapolis
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Fritz, Brandon M; Cordero, Kristy A; Barkley-Levenson, Amanda M et al. (2014) Genetic relationship between predisposition for binge alcohol consumption and blunted sensitivity to adverse effects of alcohol in mice. Alcohol Clin Exp Res 38:1284-92
Kasten, Chelsea R; Boehm 2nd, Stephen L (2014) Intra-nucleus accumbens shell injections of R(+)- and S(-)-baclofen bidirectionally alter binge-like ethanol, but not saccharin, intake in C57Bl/6J mice. Behav Brain Res 272:238-47
Thiele, Todd E; Crabbe, John C; Boehm 2nd, Stephen L (2014) "Drinking in the Dark" (DID): a simple mouse model of binge-like alcohol intake. Curr Protoc Neurosci 68:9.49.1-9.49.12
Fritz, Brandon M; Boehm 2nd, Stephen L (2014) Site-specific microinjection of Gaboxadol into the infralimbic cortex modulates ethanol intake in male C57BL/6J mice. Behav Brain Res 273:8-15
Fritz, Brandon M; Boehm 2nd, Stephen L (2014) The effect of prior alcohol consumption on the ataxic response to alcohol in high-alcohol preferring mice. Alcohol 48:765-72
Fritz, Brandon M; Companion, Michel; Boehm, Stephen L (2014) "Wired," yet intoxicated: modeling binge caffeine and alcohol co-consumption in the mouse. Alcohol Clin Exp Res 38:2269-78
Linsenbardt, David N; Boehm 2nd, Stephen L (2014) Alterations in the rate of binge ethanol consumption: implications for preclinical studies in mice. Addict Biol 19:812-25
Melon, Laverne C; Wray, Kevin N; Moore, Eileen M et al. (2013) Sex and age differences in heavy binge drinking and its effects on alcohol responsivity following abstinence. Pharmacol Biochem Behav 104:177-87
Fritz, B M; Grahame, N J; Boehm 2nd, S L (2013) Selection for high alcohol preference drinking in mice results in heightened sensitivity and rapid development of acute functional tolerance to alcohol's ataxic effects. Genes Brain Behav 12:78-86
Moore, E M; Forrest 4th, R D; Boehm 2nd, S L (2013) Genotype modulates age-related alterations in sensitivity to the aversive effects of ethanol: an eight inbred strain analysis of conditioned taste aversion. Genes Brain Behav 12:70-7

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