Abstract

Unequivocal identification of Quantitative Trait Loci (QTLs) that affect behavioral traits has been difficult, with progress limited by the behavioral and genetic complexity of these phenotypes. To circumvent complicating factors such as the effects of more than one gene, genetic interaction, etc., our strategy is to take advantage of a new genetic analytical approach, the use of congenic Recombinant Quantitative-Trait- Loci Introgression (RQI) strains, developed in our laboratory by repeated backcross-intercross cycles with concomitant selection for mesencephalic tyrosine hydroxylase activity (TH/MES, an index of number of dopamine neurons) for the genetic dissection of the murine mesotelencephalic dopamine system. We will focus on alcohol preference and alcohol-induced dopamine release in the nucleus accumbens because dopamine has been implicated in the mechanisms of alcohol-related behaviors in rodents and our preliminary results indicated significant differences both in brain dopamine systems and in alcohol preference in the progenitor and RQI strains. The overall goal of the proposal is to map and clone genes that play a pivotal role in alcohol preference. Once the QTLs are mapped and the congenic RQI strains that carry alcohol preference-QTLs are identified, a further goal of the proposal is to study the mechanism of QTL-action on a homogeneous genetic background provided by the congenic RQI lines. Identification of human homolog genes offers the potential for prevention and treatment of alcohol abuse.
Our specific aim i s (a) to map alcohol preference QTLs in sets of congenic Recombinant Quantitative- Trait-Loci introgression strains by analyzing the distribution and polymorphic microsatellite markers in the strains and investigating correlations between the markers and alcohol preference measured in a limited access paradigm, and (b) to investigate the effect of alcohol on nucleus accumbens dopamine function by in vivo microdialysis in congenic RQI strains with genetically determined high, intermediate and low alcohol preference.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA011031-02
Application #
2413270
Study Section
Special Emphasis Panel (SRCA (49))
Project Start
1996-05-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962

  Publications

Subbanna, Shivakumar; Shivakumar, Madhu; Umapathy, Nagavedi S et al. (2013) G9a-mediated histone methylation regulates ethanol-induced neurodegeneration in the neonatal mouse brain. Neurobiol Dis 54:475-85
Subbanna, Shivakumar; Shivakumar, Madhu; Psychoyos, Delphine et al. (2013) Anandamide-CB1 receptor signaling contributes to postnatal ethanol-induced neonatal neurodegeneration, adult synaptic, and memory deficits. J Neurosci 33:6350-66
Gyetvai, Beatrix; Simonyi, Agnes; Oros, Melinda et al. (2011) mGluR7 genetics and alcohol: intersection yields clues for addiction. Neurochem Res 36:1087-100
Basavarajappa, Balapal S; Nixon, Ralph A; Arancio, Ottavio (2009) Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration. Mini Rev Med Chem 9:448-62
Basavarajappa, Balapal S; Ninan, Ipe; Arancio, Ottavio (2008) Acute ethanol suppresses glutamatergic neurotransmission through endocannabinoids in hippocampal neurons. J Neurochem 107:1001-13
Basavarajappa, Balapal S (2007) Critical enzymes involved in endocannabinoid metabolism. Protein Pept Lett 14:237-46
Basavarajappa, Balapal S (2007) The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism. Mini Rev Med Chem 7:769-79
Vadasz, Csaba; Saito, Mariko; Gyetvai, Beatrix M et al. (2007) Mapping of QTLs for oral alcohol self-administration in B6.C and B6.I quasi-congenic RQI strains. Neurochem Res 32:1099-112
Vadasz, Csaba; Saito, Mariko; Gyetvai, Beatrix M et al. (2007) Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking. Genomics 90:690-702
Basavarajappa, Balapal S; Yalamanchili, Ratnakumar; Cravatt, Benjamin F et al. (2006) Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knockout mice. Neuropharmacology 50:834-44

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