Prefrontal cortex in excessive alcohol drinking: role of sigma receptors

过量饮酒中的前额皮质：西格玛受体的作用

• 批准号: 9923511
• 负责人: VALENTINA SABINO
• 金额: $ 37.13万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923511
• 关键词: Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Area; Automobile Driving; Award; Behavior; Behavior Control; Binding Sites; Boston; Brain; Brain region; Cell membrane; Chronic; Clinical Research; Cognitive deficits; Communities; Decision Making; Dendritic Spines; Disease; Endoplasmic Reticulum; Ethanol; Ethanol dependence; Etiology; Exhibits; Exposure to; Foundations; Glutamates; Goals; Heavy Drinking; Hyperactive behavior; Immunohistochemistry; Impaired cognition; Impairment; Intake; Investigation; Ligands; Measures; Mediating; Modification; Molecular; Molecular Chaperones; Morphology; Motivation; N-Methyl-D-Aspartate Receptors; National Institute on Alcohol Abuse and Alcoholism; Neuraxis; Neurobiology; Neuronal Plasticity; Neurosciences; Neurotransmitters; Patients; Pharmacological Treatment; Predisposition; Prefrontal Cortex; Rattus; Receptor Activation; Relapse; Research; Rewards; Risk-Taking; Role; Self Administration; Site; Synapses; System; Technology; Testing; Translations; Universities; Up-Regulation; Viral Vector; alcohol abuse therapy; alcohol exposure; alcohol preferring rats; alcohol response; alcohol use disorder; alcoholism therapy; cognitive function; compulsion; density; drinking; executive function; insight; knock-down; neuroadaptation; neurobiological mechanism; non-opioid analgesic; novel; pleasure; problem drinker; receptor; receptor expression; relating to nervous system; sigma receptors; sigma-1 receptor; transmission process; vapor

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.

抽象的 酒精依赖是一种以强迫性饮酒为特征的慢性复发性疾病并定义 在认知和执行功能中。饮酒成瘾的新兴照片是一种破坏的疾病 控制和强迫，而不仅仅是追求快乐。确实，酒精患者表现出 由大脑前额叶皮层区域控制的认知功能缺陷；这些障碍体现了 随着风险增加，决策不良和抑制控制的损失，他们被认为会促进 进一步饮酒。虽然证据表明慢性酒精暴露会导致行为丧失 控制，关于前段皮质区域中的神经递质系统如何不利，知之甚少 受酒精的影响以及它们如何促进更充分的饮酒易感性。 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 关注Sigma-1受体（SIG-1R），这是一种在中枢神经系统中高度表达的分子伴侣。 我们已经表明，SIG-1R的封锁减少了酒精中毒动物模型中的多余饮酒，而 它们不会减少对照大鼠中乙醇的反应或甜溶液的摄入。我们也发现 SIG-1R的激活增加了酒精的增强效率，引起了狂饮样饮酒。 Sig-1r是 在前额叶皮层中高度表达，通常执行“自上而下”抑制性控制的大脑区域 过度行为；重要的是，慢性间歇性酒精会引起Sig-1r蛋白的显着上调 前额叶区域，表明该系统的多动症可能在多余的饮酒和 在酒精成瘾中观察到的神经可塑性。 该提议的中心假设是，前偏边区域中SIG-1R的过度活跃性 介导慢性酒精引起的高易感性过度易感性。次要假设是 SIG-1R系统的这些神经适应性介导了慢性酒精引起的认知缺陷和 前额叶皮质谷氨酸能传播和树突状刺的长期修饰。 AIM 1将确定与乙醇依赖性和乙醇饮用相关的SIG-1R水平的变化， 并将确定前偏侧区域介导的SIG-1R是否超过酒精摄入量和动力 喝。 AIM 2将确定Sig-1R是否介导了慢性酒精引起的认知改变 功能，突触谷氨酸NMDA受体表达和树突状刺。 如果实现目标，我们对驱动超级酒精的神经生物学适应的理解 摄入量将大大增加，并将投资的新途径用于药物治疗 酒精使用障碍将开放。

项目成果

Pituitary adenylate cyclase-activating polypeptide (PACAP) modulates dependence-induced alcohol drinking and anxiety-like behavior in male rats

• DOI: 10.1038/s41386-020-00904-4
• 发表时间: 2020-11-16
• 期刊: NEUROPSYCHOPHARMACOLOGY
• 影响因子: 7.6
• 作者: Ferragud, Antonio;Velazquez-Sanchez, Clara;Cottone, Pietro
• 通讯作者: Cottone, Pietro

Effect of different standard rodent diets on ethanol intake and associated allodynia in male mice.

• DOI: 10.1016/j.alcohol.2020.04.003
• 发表时间: 2020-09
• 期刊: Alcohol (Fayetteville, N.Y.)
• 作者: Quadir SG;Rohl CD;Zeabi A;Moore CF;Cottone P;Sabino V
• 通讯作者: Sabino V

The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice.

• DOI: 10.1016/j.neuropharm.2020.108409
• 发表时间: 2021-02-15
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Quadir SG;Tanino SM;Rohl CD;Sahn JJ;Yao EJ;Cruz LDR;Cottone P;Martin SF;Sabino V
• 通讯作者: Sabino V