Pharmacogenetic manipulation of brain regions to reduce alcohol binge drinking

描述(由申请人提供)： 酒精依赖对个人及其家人来说是一种毁灭性的精神障碍，具有重大的医疗和社会影响。有一个严重的公共卫生需求，需要确定和确定新的和更有效的治疗方法。长期饮酒会导致奖赏和应激相关神经回路的长期变化。伏隔核(NAC)是这一回路的组成部分。与慢性酒精滥用相关的行为改变的稳定性表明，适应不良的神经可塑性可能是通过转录机制实现的。最近的临床试验表明，刺激NAC的大脑深处可以减少酒精依赖受试者的酒精渴求和复发(Vogue等人，2012年)。关于改变大脑活动的治疗方法的有效性和机制，人们还知之甚少。在拟议的研究中，我将使用DREADDS(设计师受体，由设计师药物独家激活)来增加或减少伏隔核中的神经元活动，并测量在有限获取范式中选择性培育的饮酒水平高的小鼠的酗酒行为(使用有限获取范式，在黑暗中饮酒)和复发性饮酒(使用慢性间歇性酒精诱导依赖，然后是有限获取饮酒)行为。有趣的是，初步数据显示，NAC活动的增加减少了酗酒，但不会改变酒精奖励。由于这是第一次进行这样的研究，因此确定这些行为变化是否伴随着可塑性相关基因表达的变化，并使用整个转录组测序(RNA Seq)识别DREADD/酒精反应基因表达网络将是至关重要的。这些发现可能会对酒精研究和治疗产生巨大的影响。

DESCRIPTION (provided by applicant): Alcohol dependence is a devastating psychiatric disorder to individuals and their families, with substantial medical and societal impact. There exists a serious public health need to identify and characterize new and more effective treatments. Chronic alcohol intake leads to long lasting changes in reward- and stress-related neuronal circuitry. The nucleus accumbens (NAc) is an integral component of this circuitry. The stability of behavioral alterations associated with chronic alcohol abuse suggests maladaptive neuroplasticity that is likely achieved through transcriptional mechanisms. Recent clinical trials have revealed that deep brain stimulation of the NAc decreases alcohol craving and relapse in alcohol dependent subjects (Vogues et al., 2012). Much is unknown about the efficacy and mechanisms underlying treatments that alter brain activity. In the proposed studies, I will use DREADDs (designer receptors exclusively activated by designer drugs) to increase or decrease neuronal activity in the nucleus accumbens and measure alcohol binge drinking (using the limited access paradigm, drinking in the dark) and relapse-like drinking (using chronic intermittent ethanol induction of dependence followed by limited access drinking) behaviors in mice selectively bred to drink intoxicating levels of alcohol in a limited access paradigm. Interestingly, preliminary data reveal that increasing NAc activity decreases binge drinking without altering alcohol reward. Since this is the first time a study such as this has been conducted, it will be essential to determine if these changes in behavior are accompanied by changes in expression of plasticity-related genes and identify DREADD/alcohol responsive gene expression networks using whole transcriptome sequencing (RNA Seq). These findings could have vast implications for alcohol research and treatment.