Alpha2 adrenergic receptors as a target for alcohol addiction

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，是 美国最紧迫的公共卫生问题。受澳元影响的人表现出沉重、强迫症 饮酒和无法减少或停止摄入。反复的酒精中毒循环和 禁欲会导致特定脑区的神经可塑性改变。这些问题包括 皮质-边缘区域的去甲肾上腺素(NE)系统，从而使这些区域的NE过度激活 引发并维持过度饮酒。而高NE水平的有害影响通过 α-1受体，适度去甲肾上腺素水平的有益影响似乎是由α-2介导的 肾上腺素能受体(AR)激活。事实上，阿尔法-2受体激动剂，如可乐定和胍法辛，一直是 不仅在管理酒精戒断的急性身体症状方面有效，而且还 减少酒精摄入量，恢复应激状态下的酒精寻求。而α-2受体的作用 对戒断体征的激动剂(酒精和鸦片类药物)经典的解释是激活 蓝斑(LC)内α-2受体导致中枢去甲肾上腺素(NE)活性降低， 神经适应和它们对饮酒的影响的机制尚不清楚。 这一应用的总体假设是慢性酒精诱导的去甲肾上腺素过度活动 系统(导致过量的NE释放)在CEA中产生α-2受体的下调，这在 转向会导致饮酒的驱动力增加。因此，令人痛苦的阿尔法-2ARs将允许 对酒精摄入量的“刹车”要恢复。我们的第二个假设是去甲肾上腺素过度激活的来源 在CEA是起源于孤束核(NTS，或孤束)的NE通路的过度活动 核，或A2)，投射到CEA。这些假说将通过组合的行为， 神经解剖学、分子和双病毒方法。 这项高度翻译性的研究有可能揭示导致 大量饮酒的出现，可能会为治疗AUD开辟新的途径。

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.