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: 10392187
• 负责人: Pietro Cottone
• 金额: $ 19.59万
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10392187
• 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; Attenuated; 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; Neuronal Plasticity; Neurons; Neurotransmitters; Norepinephrine; Nucleus solitarius; Opioid; Pathway interactions; Persons; Pharmacology; Public Health; Research; Research Design; Role; Sedation procedure; 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; induced hypothermia; locus ceruleus structure; nervous system disorder; neuroadaptation; norepinephrine system; 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) 是全球疾病负担的首要行为原因之一，也是其中之一 美国最紧迫的公共卫生问题受 AUD 影响的人们表现出严重的强迫性症状。 饮酒并且无法减少或停止酒精中毒的反复循环。 禁欲会导致特定大脑区域的神经塑性改变。 皮质边缘区域的去甲肾上腺素 (NE) 系统，导致这些区域的 NE 过度激活 引发并维持过量饮酒，而高 NE 水平的有害影响是通过以下途径发生的。 Alpha-1 AR，中等 NE 水平的有益作用似乎是由 Alpha-2 介导的 事实上，α-2 AR 激动剂，如可乐定和胍法辛，已被证实可以激活肾上腺素受体 (AR)。 事实证明，它不仅可以有效控制酒精戒断引起的急性身体症状，而且 减少酒精摄入和压力引起的酒精寻求恢复，而α-2 AR的影响。 激动剂对戒断体征（酒精和阿片类药物）的经典解释是通过激活 蓝斑 (LC) 内的 Alpha-2 AR，导致中枢 NE 活性降低， 神经适应及其对饮酒影响的机制尚不清楚。 本申请的总体假设是慢性酒精引起的 NE 过度活跃 系统（导致过度的 NE 释放）会导致 CeA 中 Alpha-2 AR 的下调，从而 因此，令人痛苦的 Alpha-2 AR 会导致饮酒欲望增加。 我们的次要假设是 NE 过度激活的根源。 CeA 中的 NE 通路过度活跃，起源于孤束核（NTS，或孤立束） 核，或A2）投射到CeA，这些假设将通过组合行为、 神经解剖学、分子和双病毒方法。 这项高度转化的研究有可能揭示负责的关键机制 大量饮酒的出现可能为 AUD 的治疗开辟新途径。