Alpha2 adrenergic receptors as a target for alcohol addiction

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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.