Human genetic studies have linked polymorphisms in the GABRA2 (encoding the GABA-A a2-subunit) gene to alcoholism (Edenberg et al., 2004;Soyka et al., 2008). However, the precise behavioral and neurochemical mechanism(s) for this linkage remain unclear. For example, the available evidence suggests that the GABRA2 risk allele reduces a2-subunit expression (Haughey et al., 2008), and may modulate nsk for alcoholism through alterations in the behavioral correlates impulsivity (Dick et al., 2006) and trait anxiety (Enoch et al. 2006). However, due to the complexities of studying humans, including the inability to control conditions or access the brain, the development of good animal models will be necessary to more effectively elucidate the behavioral and neurochemical mechanisms underlying the effects of the GABRA2 nsk allele.The goal of the current proposal is to investigate the mechanisms by which Gabra2 affects alcohol intake/preference, impulsive choice, and anxiety-like behavior in two different high drinking/alcohol preferring mouse populations, the C57BL/6J (B6) inbred and the high alcohol preferring (HAP2) selectively bred mouse strains/lines. A lentiviral vector-mediated delivery approach will be used to reduce (knockdown) GABA-A a2- subunit expression in several mouse brain structures believed important in the modulation of alcohol intake/preference (posterior ventral tegmental area or pVTA;nucleus accumbens shell or NACsh), impulsive choice (orbitofrontal cortex or OFC), and anxiety-like behavior (amygdala or AMY). The hypothesis is that knockdown of a2 in each of these structures will reduce alcohol intake/preference in B6 and HAP2 mice. However, the hypothesis is that the effects of a2 knockdown on the presumed impulsivity and anxiety behavioral correlates will be site-specific, with only OFC knockdown reducing impulsivity, and only AMY knockdown reducing anxiety-like behavior. Such results would further implicate altered expression of a2 as the neurochemical mechanism, and the behavioral correlates impulsivity and anxiety as the behavioral mechanisms, by which the GABRA2 genotype influences alcoholism risk.
The proposed studies will further elucidate the behavioral and neurochemical mechanisms underlying the the effects of the GABRA2 alcoholism risk genotype in humans. Such knowledge will positively impact the search for new prevention and drug treatment strategies for alcoholism.
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