No abstract

Background: Alcohol use disorder (AUD) is a complex psychiatric disease characterized by high alcohol intake as well as hyperkatifeia and hyperalgesia during withdrawal. A role for Sigma-1 receptors (Sig-1Rs) in the rewarding and reinforcing effects of alcohol has started to emerge in recent years, as rat studies have indicated that Sig-1R hyperactivity may result in excessive alcohol drinking. Sig-1R studies in mice are very scarce, and its potential role in alcohol-induced hyperalgesia is also unknown. Methods:In this study, we investigated the role of Sig-1R in alcohol drinking and associated hyperalgesia in male mice, using an intermittent access 2-bottle choice model of heavy drinking. Results:The Sig-1R antagonist BD-1063 was found dose dependently to reduce both alcohol intake and preference, without affecting either water or sucrose intake, suggesting that the effects are specific for alcohol. Notably, the ability of BD-1063 to suppress ethanol intake correlated with the individual baseline levels of alcohol drinking, suggesting that the treatment was more efficacious in heavy drinking animals.In addition, BD-1063 reversed alcohol-induced hyperalgesia during withdrawal, assessed using an automatic Hargreaves test, without affecting thermal sensitivity in alcohol-naïve animals or locomotor activity in either group.Conclusions: These data show that Sig-1R antagonism dose-dependently reduced ethanol consumption in heavy drinking mice as well as its efficacy in reducing alcoholinduced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states.

Alcohol Use Disorder (AUD) is a serious and complex neuropsychiatric disorder characterized by excessive alcohol intake, inability to control consumption, and the emergence of a negative emotional state in the absence of alcohol. While the role of the Sigma‐1 receptor (Sig‐1R) in animal models of AUD has been demonstrated, the role of Sigma‐2 receptor/Transmembrane Protein 97 (Sig‐2R/TMEM97), which has recently been cloned, is still unclear. Using an intermittent access, 2‐bottle choice paradigm, the effects of the Sig‐2R/TMEM97 modulator JVW‐1034 (0–30 mg/kg, i.p.) on ethanol drinking in male C57Bl/6J mice were assessed. Sucrose intake was used to control for non‐specific effects of the drug on an alternate reinforcer in a separate study, and locomotor intake was also assessed. In addition, using an automated von Frey filament test, the effects of JVW‐1034 on mechanical sensitivity in alcohol drinking mice was tested during withdrawal. The effects of the Sig‐2R modulator were compared to those of BD‐1063 (0–30 mg/kg, i.p.), a preferential Sig‐1R antagonist. Results showed that JVW‐1034 reduced alcohol intake and preference in this model, without affecting water intake. Sucrose intake was not affected by the drug, suggesting selectivity of the effect for alcohol. JVW‐1034 also blocked the mechanical allodynia induced by chronic alcohol drinking without affecting sensitivity in control mice. Lastly, JVW‐1034 did not affect locomotor activity in either group. BD‐1063 had a very similar profile. These data suggest that Sig‐1R and Sig‐2R play opposite roles in the regulation of alcohol drinking and associated allodynia and hyperalgesia, and lay the foundation for more extensive studies examining the involvement of the Sig‐2R/TMEM97 system in AUD.Support or Funding InformationR01‐AA024439This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.