The Sigma-2 receptor / transmembrane protein 97 (σ2R/TMEM97) modulator JVW-1034 reduces heavy alcohol drinking and associated pain states in male mice.

Alcohol Use Disorder (AUD) is a chronic relapsing disorder characterized by compulsive alcohol intake, loss of control over alcohol intake, and a negative emotional state when access to alcohol is prevented. AUD is also closely tied to pain, as repeated alcohol drinking leads to increased pain sensitivity during withdrawal. The sigma-2 receptor, recently identified as transmembrane protein 97 (σ2R/TMEM97), is an integral membrane protein involved in cholesterol homeostasis and lipid metabolism. Selective σ2R/Tmem97 modulators have been recently shown to relieve mechanical hypersensitivity in animal models of neuropathic pain as well as to attenuate alcohol withdrawal signs in C. elegans and to reduce alcohol drinking in rats, suggesting a potential key role for this protein in alcohol-related behaviors. In this study, we tested the effects of a potent and selective σ2R/TMEM97 ligand, JVW-1034, on heavy alcohol drinking and alcohol-induced heightened pain states in mice using an intermittent access model. Administration of JVW-1034 decreased both ethanol intake and preference for ethanol, without affecting water intake, total fluid intake, or food intake. Notably, this effect was specific for alcohol, as JVW-1034 had no effect on sucrose intake. Furthermore, JVW-1034 reduced both thermal hyperalgesia and mechanical hypersensitivity in ethanol withdrawn mice. Our data provide important evidence that modulation of σ2R/TMEM97 with small molecules can mediate heavy alcohol drinking as well as chronic alcohol-induced heightened pain sensitivity, thereby identifying a promising novel pharmacological target for AUD and associated pain states.

Effect of different standard rodent diets on ethanol intake and associated allodynia in male mice.

Alcohol is the most ubiquitously consumed and misused mind-altering substance in the world. Various animal models exist to aid in our neurobiological understanding of alcohol addiction. One variable too often taken for granted and not consistently controlled is the "standard" chow diet rodents are maintained on. In this set of experiments, we sought to determine the effect of different commonly used diets on ethanol intake, ethanol preference, and mechanical pain sensitivity in a widely used mouse model of heavy alcohol drinking, the intermittent access to 20% alcohol model. We found that male mice kept on LabDiet 5001 (Diet 2 [LD5001]) and on Teklad Diet 7012 (Diet 3 [H7012]) consistently drank more ethanol than mice kept on Teklad Diet 2918 (Diet 1 [H2918]) as well as compared to mice on LabDiet 5V75 (Diet 4 [LD5V75]). In addition, water intake was consistently lower in mice kept on LabDiet 5001 (Diet 2 [LD5001]), and occasionally in mice kept on Teklad Diet 7012 (Diet 3 [H7012]), compared to the Teklad Diet 2918 (Diet 1 [H2918]) group. We found that male mice showed a strong mechanical allodynia following 8 weeks of intermittent ethanol drinking at 72 h of withdrawal, compared to water Control mice, regardless of the diet and hence of the different amount of ethanol consumed. Our data provide evidence that the type of rodent diet subjects are exposed to is an important variable to report and control, in all ethanol drinking studies.