The goal of the current proposal is to provide Dr. Stephen Boehm with additional career development opportunities under the mentorship of Drs. Hitoshi Morikawa and R. Adron Harris. The excellent research environment, faculty, and facilities at the University of Texas at Austin will allow him to sharpen his skills as a young investigator, and to learn electrophysiotogical techniques for measuring GABA-A receptor currents in mouse midbrain slice. These opportunities will better prepare Dr. Boehm for a career in academic science, and compliment his expertise in neurobehavioral genetics, for example, by giving him the tools to assess the electrophysiological effects of single gene mutations in mice. Mice lacking the GABA-A alpha1 receptor subunit exhibit heightened sensitivity to ethanol's locomotor stimulant effects (Blednov et at., 2003b; Kralic et al., 2003), and alpha1 subunits are down-regulated in the ventral tegmental area (VTA) following repeated ethanol exposures (Charlton et al., 1997). The overall goals of this proposal are to 1) determine whether the alpha1 receptor subunit is important for ethanol's actions at GABAergic synapses on VTA dopamine neurons, 2) to determine whether ethanol-enhanced GABAergic current is reduced following repeated ethanol exposures that result: in behavioral (locomotor) sensitization, and 3) to establish whether alpha1 subunits are down-regulated as a result of this neuroadaptive process. We will assess several electrophysiological parameters (GABA iontophoresis, electrically-evoked IPSCs, mlPSCs) in the VTA dopamine neurons of alpha1 knock-out, knock-in, and sensitized mice. Given the role of the VTA in mediating the locomotor stimulant effects of ethanol (Imperato and DiChiara, 1986), we predict that the actions of ethanol on GABA-A receptor currents in VTA dopamine neurons of alpha1 knock-out and knock-in mice will be reduced, and that repeated exposures to ethanol producing locomotor sensitization will result in the reduced actions of ethanol and zolpidem (alpha1-selective benzodiazepine) in the VTA dopamine neurons of wild-type animals. Recent studies implicate GABA-A receptor polymorphisms in human alcoholism and understanding GABAergic modulation of alcohol activation of dopamine neurons should assist in development of pharmacotherapies for alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AA015434-04
Application #
7483753
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Liu, Qi-Ying
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$157,086
Indirect Cost
Name
State University of NY, Binghamton
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
090189965
City
Binghamton
State
NY
Country
United States
Zip Code
13902
Linsenbardt, David N; Boehm 2nd, Stephen L (2015) Relative fluid novelty differentially alters the time course of limited-access ethanol and water intake in selectively bred high-alcohol-preferring mice. Alcohol Clin Exp Res 39:621-30
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
Linsenbardt, David N; Boehm 2nd, Stephen L (2013) Determining the heritability of ethanol-induced locomotor sensitization in mice using short-term behavioral selection. Psychopharmacology (Berl) 230:267-78
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
Linsenbardt, David N; Boehm 2nd, Stephen L (2012) Role of novelty and ethanol history in locomotor stimulation induced by binge-like ethanol intake. Alcohol Clin Exp Res 36:887-94
Kruse, Lauren C; Linsenbardt, David N; Boehm 2nd, Stephen L (2012) Positive allosteric modulation of the GABA(B) receptor by GS39783 attenuates the locomotor stimulant actions of ethanol and potentiates the induction of locomotor sensitization. Alcohol 46:455-62
Linsenbardt, David N; Moore, Eileen M; Griffin, Kevar D et al. (2011) Tolerance to ethanol's ataxic effects and alterations in ethanol-induced locomotion following repeated binge-like ethanol intake using the DID model. Alcohol Clin Exp Res 35:1246-55
Melón, Laverne C; Boehm 2nd, Stephen L (2011) Role of genotype in the development of locomotor sensitization to alcohol in adult and adolescent mice: comparison of the DBA/2J and C57BL/6J inbred mouse strains. Alcohol Clin Exp Res 35:1351-60
Moore, Eileen M; Linsenbardt, David N; Melon, Laverne C et al. (2011) Ontogenetic differences in adolescent and adult C57BL/6J and DBA/2J mice: anxiety-like, locomotor, and consummatory behaviors. Dev Psychobiol 53:141-56
Moore, Eileen M; Mariani, John N; Linsenbardt, David N et al. (2010) Adolescent C57BL/6J (but not DBA/2J) mice consume greater amounts of limited-access ethanol compared to adults and display continued elevated ethanol intake into adulthood. Alcohol Clin Exp Res 34:734-42

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