Effect of Gabra2 Knockdown on Alcohol Preference

人类遗传学研究已经将GABRA 2（编码GABA-A α 2-亚基）基因的多态性联系起来 酒精中毒（Edenberg等人，2004; Replika等人，2008年）。然而，精确的行为和 这种联系的神经化学机制仍不清楚。例如，现有证据表明， GABRA 2危险等位基因降低α 2-亚基表达（Haughey等，2008年），并可能调制nsk 通过改变行为相关的冲动性来治疗酒精中毒（Dick等人，（2006）焦虑 （以诺等人，2006年）。然而，由于研究人类的复杂性，包括无法控制 条件或进入大脑，良好的动物模型的发展将是必要的，更有效地 阐明GABRA 2 nsk作用的行为和神经化学机制 当前提议的目标是研究Gabra 2影响酒精的机制。 在两个不同的高饮酒/酒精偏好的摄入/偏好，冲动的选择，和焦虑样行为 小鼠群体、C57 BL/6 J（B6）近交系和高度酒精偏好（HAP 2）选择性繁殖的小鼠 菌株/品系。将使用慢病毒载体介导的递送方法来减少（敲低）GABA-A α 2。 几种小鼠脑结构中的亚基表达被认为在酒精调节中很重要 摄入/偏好（后腹侧被盖区或pVTA;丘脑核壳或NACsh），冲动 选择（眶额皮质或OFC）和焦虑样行为（杏仁核或AMY）。前提是 在这些结构中的每一个中敲低α 2将减少B6和HAP 2小鼠中的酒精摄入/偏好。 然而，假设a2基因敲低对假定的冲动性和焦虑性的影响 行为相关性将是特定于地点的，只有OFC敲除降低冲动性，只有AMY 击倒减少焦虑样行为。这样的结果将进一步暗示a2的表达改变， 神经化学机制，以及行为相关的冲动和焦虑， GABRA 2基因型影响酒精中毒风险的机制。

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.