Prefrontal cortex in excessive alcohol drinking: role of sigma receptors

摘要 酒精依赖是一种慢性复发性疾病，其特征是强迫性饮酒和酒精缺乏 认知和执行功能。酒精成瘾的新形象是一种精神紊乱的疾病 控制和强迫，而不仅仅是追求快乐。事实上，酗酒者会表现出 由大脑前额皮质区域控制的认知功能缺陷；这些缺陷表现出来 由于冒险行为的增加、决策失误和抑制控制的丧失，它们被认为会促进 进一步过量饮酒。虽然有证据表明长期接触酒精会导致行为能力丧失 控制，我们对前额皮质区域的神经递质系统如何受到不利影响知之甚少 受酒精的影响以及它们如何导致过度饮酒的易感性。 该项目将在位于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（Sig-1R），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 它们不会减少对照大鼠对乙醇的反应或甜溶液的摄入。我们还发现 Sig-1R 的激活会增加酒精的强化功效，从而引发暴饮暴食。 Sig-1R 是 在前额皮质中高度表达，该区域通常发挥“自上而下”的抑制控制作用 过度行为；重要的是，长期间歇性饮酒会导致 Sig-1R 蛋白急剧上调 前额叶区域，表明该系统的过度活跃可能在过度饮酒和 在酒精成瘾中观察到的神经可塑性。 该提议的中心假设是前额皮质区域 Sig-1R 的过度活跃 介导慢性酒精引起的过度饮酒的高易感性。第二个假设是 Sig-1R 系统的这些神经适应介导慢性酒精引起的认知缺陷 前额皮质谷氨酸传输和树突棘的持久改变。 目标 1 将确定与乙醇依赖和乙醇饮用相关的 Sig-1R 水平的变化， 并将确定前额皮质区域的 Sig-1R 是否介导过量饮酒和动机 喝。目标 2 将确定 Sig-1R 是否介导慢性酒精引起的认知改变 功能、突触谷氨酸 NMDA 受体表达以及前额皮质区域的树突棘。 如果目标实现，我们对导致过量饮酒的神经生物学适应的理解 摄入量将显着增加，并且研究药物治疗的新途径 酒精使用障碍就会出现。

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.