Oxytocin Reduces Ethanol Self‐Administration in Mice

Abstract

Background Excessive ethanol consumption remains an important health concern and effective treatments are lacking. The central oxytocin system has emerged as a potentially important therapeutic target for alcohol and drug addiction. These studies tested the hypothesis that oxytocin reduces ethanol consumption. Methods Male C57BL/6J mice were given access to ethanol (20% v/v) using a model of binge-like drinking (“drinking-in-the-dark”) that also included the use of lickometer circuits to evaluate the temporal pattern of intake as well as 2-bottle choice drinking in the home cage. In addition, ethanol (12% v/v) and sucrose (5% w/v) self-administration on fixed- and progressive- ratio schedules were also evaluated. A wide range of systemically administered oxytocin doses were tested (0 to 10 mg/kg) in these models. Results Oxytocin (0, 0.3, 1, 3 or 10mg/kg) dose-dependently reduced ethanol consumption (maximal 45% reducton) in the binge drinking model, with lower effective doses having minimal effects on general locomotor activity. Oxytocin’s effect was blocked by pretreatment with an oxytocin receptor antagonist and the pattern of contacts (licks) at the ethanol bottle suggested a reduction in motivation to drink ethanol. Oxytocin decreased 2-bottle choice drinking without altering general fluid intake. Oxytocin also reduced operant responding for ethanol and sucrose in a dose-related manner. However, oxytocin decreased responding and motivation (breakpoint values) for ethanol at doses that did not alter responding for sucrose. Discussion These results indicate that oxytocin reduces ethanol consumption in different models of self-administration. The effects are not likely due to a general sedative effect of the neuropeptide. Further, oxytocin reduces motivation for ethanol at doses that do not alter responding for a natural reward (sucrose). While some evidence supports a role for oxytocin receptors in mediating these effects, additional studies are needed to further elucidate underlying mechanisms. Neverthess, these results support the therapeutic potential of oxytocin as a treatment for alcohol use disorder.

Oxytocin and Rodent Models of Addiction

“…In more recent reports, systemic administration of oxytocin has been shown to reduce alcohol preference and intake in a variety of voluntary drinking models in rats (Bowen, Carson, Spiro, Arnold, & McGregor, 2011; MacFadyen et al, 2016; McGregor & Bowen, 2012) and mice (King et al, 2017; Peters, Slattery, Flor, Neumann, & Reber, 2013). Specifically, McGregor and Bowen (2012) found that a single dose of oxytocin (1mg/kg) produced a long-lasting reduction in preference for an alcohol-containing solution compared with a nonalcoholic sweet solution.…”

“…MacFadyen et al (2016) reported that systemic administration of a lower dose range of oxytocin (0.1–0.5mg/kg; ip) reduced operant alcohol self-administration in rats. Further, in alcohol-preferring C57BL/6J mice, systemic administration of oxytocin decreased alcohol self-administration and binge-like alcohol consumption in a dose-related manner (0.3, 1, 3 or 10 mg/kg; ip), as well as reduced motivation for alcohol reward as measured by responding under a PR schedule (King et al, 2017). Peripheral oxytocin treatment in a similar dose range (1–10mg/kg) reduced alcohol consumption in male and female prairie voles that had two-bottle choice free-access to 15% alcohol (Stevenson, Wenner, et al, 2017).…”

“…Recent reports showed that viral-mediated overexpression of oxytocin receptors in NAc reduced alcohol-induced conditioned place preference and alcohol consumption in mice (Bahi, 2015; Bahi, Al Mansouri, & Al Maamari, 2016). Additionally, the ability of oxytocin to reduce binge-like alcohol drinking was blocked by pre-treatment with an oxytocin receptor antagonist, suggesting that oxytocin reduced alcohol consumption via interaction with its own receptor (King et al, 2017). While the oxytocin receptor appears to be involved in the rewarding effects of alcohol, it is important to note that Bowen and colleagues showed that attenuation of sedative and ataxic effects by central oxytocin administration was mediated by GABA A receptors (Bowen et al, 2015).…”

Influence of stress associated with chronic alcohol exposure on drinking

“…For example, systemic administration of oxytocin reduces alcohol preference and intake in a variety of drinking models in rats (Bowen et al, 2011; MacFadyen et al, 2016; McGregor and Bowen, 2012) and mice (King et al, 2017; Peters et al, 2013). Direct injection of oxytocin into brain ventricles reduced alcohol consumption and alcohol-induced dopamine efflux in the nucleus accumbens in rats (Peters et al, 2016).…”

M5 Muscarinic Receptor Gene Deletion Accelerates Extinction, But Inhibits Reinstatement of Morphine-Conditioned Reward in Mice

“…Better understanding of the factors that influence renewed drug-seeking, and the persistent craving for drugs, is needed. Studying mouse models of extinction and relapse may help identify molecular mechanisms of brain plasticity in drug addiction [11][12][13][14].…”