Prefrontal cortex in excessive alcohol drinking: role of sigma receptors

摘要 酒精依赖是一种慢性复发性障碍，其特征是强迫性饮酒和酒精缺乏。 在认知和执行功能上。酒精成瘾的新图景是一种精神错乱的疾病 控制和强迫，而不仅仅是对快乐的追求。事实上，酗酒患者表现出 由大脑的前额叶皮质区域支配的认知功能的缺陷；这些损伤明显 因为更多的冒险，糟糕的决策，以及失去抑制性控制，他们被认为促进了 进一步过度饮酒。而有证据表明，长期饮酒会导致行为障碍 对于前额叶皮质区域的神经递质系统如何产生不利影响，我们知之甚少。 酒精的影响及其对过度饮酒易感性的影响。 这个项目将在波士顿丰富的神经科学社区的波士顿大学进行， 涉及Sigma-1受体(Sigma-1R)，它是一种在中枢神经系统中高度表达的分子伴侣。 我们已经证明，阻断SIG-1R可以减少酒精中毒动物模型中的过度饮酒，而 它们不会减少对照组大鼠对酒精的反应，也不会减少甜味溶液的摄入量。我们还发现了 SIG-1R的激活增加了酒精的强化效果，引发了类似狂欢的饮酒。SIG-1R是 在前额叶皮质中高表达，这是一个正常情况下实施“自上而下”抑制控制的大脑区域 行为过度；重要的是，慢性间歇性酒精导致脑内SIG-1R蛋白表达显著上调 前额叶区域，这表明该系统的过度活动可能在过量饮酒和 酒精成瘾时观察到的神经可塑性。 这一建议的中心假设是前额叶皮质区域SIG-1R的过度活动 调节慢性酒精诱导的过度饮酒的高敏感性。第二个假设是 SIG-1R系统的这些神经适应调节介导了慢性酒精诱导的认知障碍和 前额叶-皮质谷氨酸能传递和树突棘的长期修饰。 目标1将确定与酒精依赖和饮酒相关的Sig-1R水平的变化， 并将确定前额叶皮质区域的SIG-1R是否调节过量酒精摄入和动机 喝一杯。目标2将确定Sig-1R是否介导慢性酒精诱导的认知改变 功能，突触谷氨酸NMDA受体的表达，以及前额叶皮质区域的树突棘。 如果这些目标实现了，我们对过度饮酒的神经生物学适应的理解 摄入量将显著增加，并为药物治疗提供新的研究途径 酒精使用障碍将会打开。

ABSTRACT Alcohol dependence is a chronic relapsing disorder characterized by compulsive alcohol use and deficits in cognitive and executive functions. The emerging picture of alcohol addiction is that of a disease of disrupted control and compulsion, rather than merely of the pursuit of pleasure. Indeed, alcoholic patients exhibit deficits in cognitive functions governed by prefronto-cortical regions of the brain; these impairments manifest as increased risk taking, poor decision making, and loss of inhibitory control and they are thought to promote further excessive drinking. While evidence shows that chronic alcohol exposure results in loss of behavioral control, little is known about how neurotransmitter systems in prefronto-cortical regions are adversely impacted by alcohol and how they contribute to the susceptibility to drink excessively. This project, to be conducted at Boston University in the rich neuroscience community of Boston, concerns Sigma-1 receptor (Sig-1R), a molecular chaperone highly expressed in the central nervous system. We have shown that blockade of Sig-1R reduce excessive drinking in animal models of alcoholism, while they do not reduce responding for ethanol in control rats or the intake of sweet solutions. We have also found that activation of Sig-1R increases the reinforcing efficacy of alcohol, inducing binge-like drinking. Sig-1Rs are highly expressed in the prefrontal cortex, a brain area which normally exerts “top-down” inhibitory control over behavior; importantly chronic intermittent alcohol causes a dramatic up-regulation of Sig-1R protein in prefrontal regions, suggesting that hyperactivity of this system may have a key role in excessive drinking and in the neuroplasticity observed in alcohol addiction. The central hypothesis of this proposal is that hyperactivity of Sig-1R in prefronto-cortical regions mediates the chronic alcohol-induced high susceptibility to drink excessively. A secondary hypothesis is that these neuroadaptations of the Sig-1R system mediate chronic alcohol-induced cognitive deficits and the long-lasting modifications of prefronto-cortical glutamatergic transmission and dendritic spines. Aim 1 will identify changes in Sig-1R levels associated with ethanol-dependence and ethanol drinking, and will determine whether Sig-1R in prefronto-cortical areas mediates excessive alcohol intake and motivation to drink. Aim 2 will determine whether Sig-1R mediates chronic alcohol-induced alterations in cognitive function, synaptic glutamate NMDA receptor expression, and dendritic spines in prefronto-cortical areas. If the aims are achieved, our understanding of the neurobiological adaptations driving excessive alcohol intake would significantly increase and new avenues of investigation towards the pharmacological treatment of alcohol use disorders would open.