Alpha2 adrenergic receptors as a target for alcohol addiction

α2 肾上腺素能受体作为酒精成瘾的靶点

• 批准号: 10557791
• 负责人: Pietro Cottone
• 金额: $ 23.72万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557791
• 关键词: Acute; Addictive Behavior; Adrenergic Receptor; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholism; Alcohols; Amygdaloid structure; Area; Astrocytes; Behavioral; Belief; Binding; Brain region; Cardiovascular system; Cell Nucleus; Cells; Chronic; Clinic; Clonidine; Corticotropin-Releasing Hormone; Data; Designer Drugs; Development; Dopamine-beta-monooxygenase; Down-Regulation; Drug abuse; Dynorphins; Ethanol; Foundations; Goals; Guanfacine; Heavy Drinking; Human; Hyperactivity; Immunohistochemistry; Impairment; Intake; Light; Maintenance; Mediating; Mental disorders; Molecular; Motivation; Mus; Neuroanatomy; Neuronal Plasticity; Neurons; Neurotransmitters; Norepinephrine; Nucleus solitarius; Opioid; Pathway interactions; Persons; Public Health; Research; Research Design; Role; Sedation procedure; Shapes; Source; Stress; Sucrose; System; Testing; Therapeutic Agents; Tracer; Translational Research; United States; Viral; Virus; Withdrawal; alcohol abstinence; alcohol abuse therapy; alcohol seeking behavior; alcohol use disorder; burden of illness; density; drinking; high reward; high risk; locus ceruleus structure; natural hypothermia; nervous system disorder; neuroadaptation; norepinephrine system; pharmacologic; physical symptom; protein kinase C-delta; receptor; sedative; selective expression; side effect; transmission process

ABSTRACT Alcohol use disorder (AUD) is one of the top behavioral causes of global disease burden and is among the most pressing public health concerns in the United States. People affected by AUD show heavy, compulsive alcohol drinking and an inability to reduce or stop intake. Repeated cycles of alcohol intoxication and abstinence induce neuroplastic alterations in specific brain regions. These include the disruption of the norepinephrine (NE) system in cortico-limbic areas, such that excessive NE activation in these areas then triggers and sustains excessive alcohol drinking. While the detrimental effects of high NE levels occur via Alpha-1 AR, the beneficial effects of moderate NE levels appear instead to be mediated by Alpha-2 adrenoceptor (AR) activation. Indeed, Alpha-2 AR agonists, such as clonidine and guanfacine, have been shown not only to be effective in the management of acute, physical symptoms of alcohol withdrawal, but also to reduce alcohol intake and stress-induced reinstatement of alcohol seeking. While the effects of alpha-2 AR agonists on physical signs of withdrawal (both alcohol and opiates) are classically explained by the activation of Alpha-2 ARs within the locus coeruleus (LC), which results in decreased central NE activity, the neuroadaptations and mechanisms responsible for their effects on alcohol drinking are unknown. The overall hypothesis of this application is that the chronic alcohol-induced hyperactivity of NE systems (resulting in excessive NE release) produces a down-regulation of Alpha-2 ARs in the CeA, which in turn would cause an increased drive to drink alcohol. Therefore, agonizing Alpha-2 ARs would allow the “brake” on alcohol intake to be restored. Our secondary hypothesis is that source of the excessive NE activation in CeA is the hyperactivity of the NE pathway originating in the Nucleus Tractus Solitarii (NTS, or solitary tract nucleus, or A2) which projects to the CeA. These hypotheses will be tested by means of a combined behavioral, neuroanatomical, molecular, and dual-viral approach. This highly translational research has the potential to shed light onto key mechanisms responsible for the emergence of heavy drinking and may open new avenues for the treatment of AUD.

抽象的 酒精使用障碍（AUD）是全球疾病伯恩的主要行为原因之一，是 美国最紧迫的公共卫生问题。受校大影响的人表现出沉重的强迫性 饮酒，无法减少或停止摄入量。重复的酒精中毒和 禁欲诱导特定大脑区域的神经塑性改变。这些包括破坏 皮质膜区域中的去甲肾上腺素（NE）系统，使得这些区域的过量激活 触发和自杀过量饮酒。高NE水平的不利影响通过 alpha-1 ar，现代化水平的有益作用似乎是由alpha-2介导的 adrenoceptor（AR）激活。确实，α-2 AR激动剂，例如可乐定和鸟汀，已经是 不仅表明有效地管理急性戒酒的身体症状，而且还具有 减少酒精摄入量和应力引起的饮酒恢复。而alpha-2 ar的影响 戒断物的身体迹象（酒精和优化）的激动剂通过激活的激活来解释 位点凝固层（LC）内的alpha-2 Ars，导致中央NE活性降低， 神经照射和负责其对饮酒影响的机制尚不清楚。 该应用的总体假设是慢性酒精诱导的NE的多动症 系统（导致NE释放过多）在CEA中产生α-2 AR的下调 转弯会导致饮酒的动力增加。因此，痛苦的alpha-2 ars将允许 酒精摄入量的“制动”要恢复。我们的次要假设是过量NE激活的来源 在CEA中，是源自核心核（NTS或固体道）的NE途径的多动症 核或A2）将其投射到CEA。这些假设将通过联合行为进行检验， 神经解剖学，分子和双病毒方法。 这项高度翻译的研究有可能阐明负责的关键机制 大量饮酒的出现，可能为AUD治疗开辟新的途径。