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庭来说是一种毁灭性的精神疾病，具有重大的医疗和社会影响。公共卫生迫切需要确定和描述新的和更有效的治疗方法。长期酒精摄入导致奖励和压力相关神经元回路的长期变化。脑桥核（NAc）是这个回路的组成部分。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。最近的临床试验已经揭示，NAc的脑深部刺激降低了酒精依赖受试者的酒精渴望和复发（Vogues等人，2012年）。关于改变大脑活动的治疗方法的疗效和机制还知之甚少。在拟议的研究中，我将使用DREADDs（设计师受体专门由设计师药物激活），以增加或减少丘脑核中的神经元活动，并测量酗酒（使用受限访问范例，在黑暗中饮酒）和复发性饮酒（使用慢性间歇性乙醇诱导依赖，然后限制饮用）在一个有限的访问范例中，选择性地饲养小鼠以饮用致醉水平的酒精。有趣的是，初步数据显示，增加NAc活性可以减少酗酒，而不会改变酒精奖励。由于这是第一次进行这样的研究，因此必须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，并使用全转录组测序（RNA Seq）鉴定DREADD/酒精反应基因表达网络。这些发现可能对酒精研究和治疗产生巨大影响。

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.