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.