Orexin modulation of brain reward-brain stress system interactions in alcohol withdrawal anxiety

Alcohol use disorder (AUD) affects ~17 million Americans, contributing to more than 2.5 million deaths each year
in the United States alone and costing the United States $249 billion annually. Humans with AUD often
experience negative affect during withdrawal (WD), and depressed mood and anxiety are positively correlated
with relapse during abstinence. The neurobiological mechanisms underlying an individual’s response to alcohol,
and his/her propensity to develop AUD, are not entirely understood. Acute and chronic alcohol alter
neurotransmission in mesocorticolimbic circuitry, including the ventral tegmental area (VTA), and chronic alcohol
also alters neurotransmission in the central amygdala (CeA), an area involved in increased anxiety during WD.
There is a functional connection between the VTA and CeA, and although each of these regions is important for
addictive behavior, the role of the connection between them in addictive behaviors is unknown. Our preliminary
data indicate that alcohol WD activates the VTA-CeA circuit in alcohol-dependent animals. The goal of this K01
proposal is to determine the mechanism underlying this circuit activation, as well as the contribution of the circuit
to increased anxiety-like behavior during WD. The overarching hypothesis of this proposal is that CeA-projecting
VTA dopamine (DA) neurons become activated during alcohol WD via an orexin 1 receptor (OX1R)-mediated
mechanism, and that activation of this circuit is critical in the development of dependence-associated increased
anxiety-like behavior during acute WD. To test this hypothesis, the proposal will utilize a combination of
anatomical, cellular, imaging, circuit-based and behavioral techniques. This proposal will provide a promising
young scientist with vital research training and professional development opportunities facilitated by experiments
that use an integrative approach to test the predictions that: (1) increased VTA-CeADA activity observed in vitro
during WD from chronic alcohol is mediated by OX1R/endocannabinoid (eCB) signaling, (2) that increased CeA
activity observed in vivo during WD from chronic alcohol is mediated by increased DA input from the VTA, and
(3) that VTA OX1R/eCB signaling mediates alcohol WD-induced anxiety-like behavior. The results of these
studies will open new avenues of neuroscientific investigation exploring the crosstalk between brain reward and
brain stress systems in addiction. This work may also inform development of treatment strategies for reducing
negative affective symptoms in individuals with AUD, leading to improvements in quality of life and health of
affected individuals, and decreasing morbidity associated with these disorders.

Grant Number: 5K01AA028541-05
NIH Institute/Center: NIH
Principal Investigator: Elizabeth Avegno