Alcohol misuse is responsible for ~88,000 deaths annually and exerts an annual cost of ~$250 billion in the US. Binge drinking, which accounts for ~75% of these costs, is defined by the National Institute on Alcohol Abuse and Alcoholism as consuming 4-5 drinks and/or achieving a blood alcohol level >80 mg/dL within a 2 hr period (Sacks et al., 2010). Binge drinking is increasing in the US, is highly prevalent in both male and female active military duty personnel and veterans, and is a strong predictor of an alcohol use disorder (AUD; Han et al., 2017; Stahre et al., 2009; Gowin et al., 2017). More than 40% of US military veterans have a lifetime history of alcohol use disorder (Fuerlein et al., 2016). Thus, alcohol exerts a large burden on health, social, and economic problems, especially within the Department of Veterans Affairs. How individuals respond to their first experiences with alcohol are related to their risk for developing an AUD, including frequent early adult binge drinking (King et al., 2011; McCarty et al., 2004). Identifying the brain circuitry that underlies this dangerous pattern of drinking is an important first step in learning about vulnerability factors for AUD. Our recent studies identified a key role for the nucleus accumbens (NAc) core in binge-like drinking using DID (Drinking in the Dark; a paradigm which models binge-like drinking in mice) and chemogenetics [i.e. DREADDs (designer receptors exclusively activated by designer drugs)]. Circuitry-based studies in animals are powerfully relevant for humans with AUD. Treatment-resistant males with an AUD diagnosis exhibit reduced drinking, craving, and rates of relapse with deep brain stimulation of the NAc (Pierce and Vassoler, 2013). The NAc core receives projections from several regions and is important for many behaviors. To further understand the circuitry of binge drinking, we will identify neural projections to the NAc core that are engaged during DID in high drinking C57BL/6J mice. We will inject the retrograde marker, rAAVretro-GFP, into the NAc core, expose mice to ethanol, saccharin, or water DID procedures, and then quantify c-Fos immunoreactivity in GFP positive neurons. The proposed work will be the first to identify the NAc core circuitry engaged during binge drinking using both in males and females. We hypothesize that several NAc projecting brain regions will be engaged during ethanol DID, including the central and basolateral amygdala, prelimbic cortex, and insula, ventral tegmental area, and ventral hippocampus. Our preliminary data support testing the role of an understudied projection from the central nucleus of the amygdala (CeA) to the NAc core in binge drinking. Both regions are well known to be involved in alcohol drinking, yet very little is known about the nature and role of this projection in drinking. We will manipulate CeA inputs to the NAc (via chemogenetics and dual virus projection targeting) to determine whether this projection modulates binge-like drinking. CeA neurons contain many neuropeptides and modulators; therefore, we will identify the nature of these projections using immunohistochemistry. Based on the literature and the results of our preliminary studies, we focus on the peptide neurotransmitter, corticotropin releasing factor (CRF). We will administer corticotropin releasing factor (CRF) intra-accumbens to determine whether it alters binge-like drinking. We will then test whether antagonism of CRF receptors can block the effects of stimulating CeA- >NAc core projections (via chemogenetics) on DID. We hypothesize that chemogenetic stimulation of CeA- >NAc projections will reduce drinking, intra-NAc core CRF will reduce binge-like drinking, and intra-NAc CRF antagonists will block reductions in drinking seen with chemogenetic stimulation of CeA->NAc core projections. This proposal will use behavioral, pharmacological, and circuitry based approaches to better understand the neural substrates of binge drinking. We will identify neuronal projections to NAc core important for regulating binge-like drinking in the high drinking C57BL/6J mouse strain. We hypothesize that CeA projections to the NAc core are important for regulating binge drinking and are engaged by binge drinking.
Alcohol is the 3rd leading cause of preventable death in the US, and binge drinking has an economic burden of $186 billion/year. Binge drinking is highly prevalent in active military duty personnel and veterans. More than 40% of military veterans have a lifetime history of alcohol use disorder (AUD). Thus, alcohol misuse exerts a large burden, especially within the VA. How individuals respond to their first experiences with alcohol is related to their risk for developing an AUD, including frequent early adult binge drinking (King et al., 2011; McCarty et al., 2004). Understanding the brain circuitry that underlies this dangerous pattern of drinking is an important first step in learning about vulnerability factors for AUD. We propose to identify brain regions engaged during binge drinking and manipulate specific brain circuits to determine what role they play in binge drinking. We will learn which circuits are engaged early, and this informs us of mechanisms that are involved in risk for AUD. If we can block them, then we are interfering with a mechanism important for risk for AUD.
