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.

摘要 酒精使用障碍（AUD）是全球疾病负担的主要行为原因之一， 美国最紧迫的公共卫生问题。受AUD影响的人表现出沉重，强迫性 饮酒和无法减少或停止摄入。反复的酒精中毒和 禁欲会导致特定脑区的神经可塑性改变。其中包括破坏 去甲肾上腺素（NE）系统在皮质边缘区，使过度NE激活，在这些地区，然后 引发并维持过量饮酒。虽然高NE水平的有害影响是通过 α-1 AR，中等NE水平的有益作用似乎是由α-2介导的 肾上腺素受体（AR）激活。事实上，α-2 AR激动剂，如可乐定和胍法辛，已经被广泛应用。 不仅能有效治疗酒精戒断的急性身体症状， 减少酒精摄入量和压力引起的酒精寻求恢复。虽然α-2 AR的作用 激动剂对戒断体征（酒精和阿片类药物）的作用经典地解释为激活 蓝斑（LC）内的α-2 AR导致中枢NE活性降低， 神经适应和机制，负责其对饮酒的影响是未知的。 本申请的总体假设是，慢性酒精诱导的NE过度活跃 系统（导致过量NE释放）在CeA中产生α-2 AR的下调， 会增加饮酒的冲动。因此，痛苦的Alpha-2 AR将允许 酒精摄入量的“刹车”需要恢复。我们的第二个假设是NE过度激活的来源 在CeA中是起源于孤束核（NTS，或孤束）的NE通路的过度活跃 核，或A2），其投射到CeA。这些假设将通过结合行为， 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 大量饮酒的出现，并可能为治疗AUD开辟新的途径。