Abstract
Excessive, binge alcohol drinking is a potent and pernicious obstacle to treating alcohol use disorder (AUD), and heavy-drinking humans are responsible for much of the substantial costs and harms of AUD. Thus, identifying key mechanisms that drive intake in higher-drinking individuals may provide important, translationally useful therapeutic interventions. Orexin-1-receptors (Ox1Rs) promote states of high motivation, and studies with systemic Ox1R inhibition suggest a particular role in individuals with higher intake levels. However, little has been known about circuits where Ox1Rs promote pathological intake, especially excessive alcohol consumption. We previously discovered that binge alcohol drinking requires Ox1Rs in medial nucleus accumbens shell (Shell), using two-bottle-choice Drinking-in-the-Dark (2bc-DID) in adult, male C57BL/6 mice. Here, we show that Shell Ox1Rs promoted intake during intermittent-access alcohol drinking as well as 2bc-DID, and that Shell inhibition with muscimol/baclofen also suppressed 2bc-DID intake. Importantly, with this large data set, we were able to demonstrate that Shell Ox1Rs and overall activity were particularly important for driving alcohol consumption in higher-drinking individuals, with little overall impact in moderate drinkers. Shell inhibition results were compared with control data combined from drug treatments that did not reduce intake, including NMDAR or PKC inhibition in Shell, Ox1R inhibition in accumbens core, and systemic inhibition of dopamine-1 receptors; these were used to understand whether more specific Shell Ox1R contributions in higher drinkers might simply result from intrinsic variability in mouse drinking. Ineffectiveness of Shell inhibition in moderate-drinkers was not due to a floor effect, since systemic baclofen reduced alcohol drinking regardless of basal intake levels, without altering concurrent water intake or saccharin consumption. Finally, alcohol intake in the first exposure predicted consumption levels weeks later, suggesting that intake level may be a stable trait in each individual. Together, our studies indicate that Shell Ox1Rs are critical mediators of binge alcohol intake in higher-drinking individuals, with little net contribution to alcohol drinking in more moderate bingers, and that targeting Ox1Rs may substantially reduce AUD-related harms.
Highlights
We show that Shell Orexin-1-type receptors (Ox1Rs) are critical promoters of increased intake in higher-drinking individuals, and might represent a potent translational target to reduce the harms of human binge alcohol intake and alcohol use disorder (AUD)
We previously demonstrated that Shell Ox1Rs promote 2bc-DID drinking (Lei et al, 2016b), and that animals drinking under this model reach binge-level blood alcohol concentrations (Lei et al, 2016a)
To further understand how the Shell contributes to alcohol intake, we examined whether inhibiting the Shell with muscimol/baclofen (M/B, 50 ng of each/side), which produces more global inhibition of activity (Chaudhri et al, 2010; Millan et al, 2010; Wilden et al, 2014), would reduce 2bc-DID intake
Summary
Binge-level alcohol consumption is a major obstacle when treating alcohol use disorder (AUD) (Harwood et al, 1998; Larimer et al, 1999; Blincoe et al, 2002; Mokdad et al, 2004; Dawson et al, 2005; Hingson et al, 2005; Rehm et al, 2009; Koob and Volkow, 2010; Bouchery et al, 2011; Sacks et al, 2013; Center for Disease Control and Prevention [CDC], 2014; Substance Abuse and Mental Health Services Administration [SAMHSA], 2014). Orexin signaling has been identified as being of particular importance for driving many motivation- and addiction-related behaviors (Mahler et al, 2012, 2014; Boutrel et al, 2013; Barson and Leibowitz, 2016; James et al, 2017). Ox1Rs could be a novel intervention to treat AUD and other motivational disorders (Khoo and Brown, 2014; Li et al, 2016)
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