• Energy Research
• 2016-2025close

The Sigma-1 receptor (Sig-1R) is a chaperone protein that has been implicated in drug abuse and addiction. Multiple studies have characterized the role the Sig-1R plays in psychostimulant addiction; however, fewer studies have specifically investigated its role in alcohol addiction. We have previously shown that antagonism of the Sig-1R reduces excessive drinking and motivation to drink, whereas agonism induces binge-like drinking in rodents.The objectives of these studies were to investigate the impact of Sig-1R gene deletion in C57Bl/6J mice on ethanol drinking and other ethanol-related behaviors.We used an extensive panel of behavioral tests to examine ethanol actions in male, adult mice lacking Oprs1, the gene encoding the Sig-1R. To compare ethanol drinking behavior, Sig-1 knockout (KO) and wild type (WT) mice were subject to a two-bottle choice, continuous access paradigm with different concentrations of ethanol (3-20% v/v) vs. water. Consumption of sweet and bitter solutions was also assessed in Sig-1R KO and WT mice. Finally, motor stimulant sensitivity, taste aversion and ataxic effects of ethanol were assessed.Sig-1R KO mice displayed higher ethanol intake compared to WT mice; the two genotypes did not differ in their sweet or bitter taste perception. Sig-1R KO mice showed lower sensitivity to ethanol stimulant effects, but greater sensitivity to its taste aversive effects. Ethanol-induced sedation was instead unaltered in the mutants.Our results prove that the deletion of the Sig-1R increases ethanol consumption, likely by decreasing its rewarding effects, and therefore indicating that the Sig-1R is involved in modulation of the reinforcing effects of alcohol.

The Sigma-1 receptor (Sig-1R) is a chaperone protein that has been implicated in drug abuse and addiction. Multiple studies have characterized the role the Sig-1R plays in psychostimulant addiction; however, fewer studies have specifically investigated its role in alcohol addiction. We have previously shown that antagonism of the Sig-1R reduces excessive drinking and motivation to drink, whereas agonism induces binge-like drinking in rodents.The objectives of these studies were to investigate the impact of Sig-1R gene deletion in C57Bl/6J mice on ethanol drinking and other ethanol-related behaviors.We used an extensive panel of behavioral tests to examine ethanol actions in male, adult mice lacking Oprs1, the gene encoding the Sig-1R. To compare ethanol drinking behavior, Sig-1 knockout (KO) and wild type (WT) mice were subject to a two-bottle choice, continuous access paradigm with different concentrations of ethanol (3-20% v/v) vs. water. Consumption of sweet and bitter solutions was also assessed in Sig-1R KO and WT mice. Finally, motor stimulant sensitivity, taste aversion and ataxic effects of ethanol were assessed.Sig-1R KO mice displayed higher ethanol intake compared to WT mice; the two genotypes did not differ in their sweet or bitter taste perception. Sig-1R KO mice showed lower sensitivity to ethanol stimulant effects, but greater sensitivity to its taste aversive effects. Ethanol-induced sedation was instead unaltered in the mutants.Our results prove that the deletion of the Sig-1R increases ethanol consumption, likely by decreasing its rewarding effects, and therefore indicating that the Sig-1R is involved in modulation of the reinforcing effects of alcohol.

AbstractBackgroundAlcohol 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.MethodsIn 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.ResultsThe 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.ConclusionsThese data show that Sig‐1R antagonism dose‐dependently reduced ethanol consumption in heavy drinking mice as well as its efficacy in reducing alcohol‐induced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states.

AbstractBackgroundAlcohol 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.MethodsIn 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.ResultsThe 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.ConclusionsThese data show that Sig‐1R antagonism dose‐dependently reduced ethanol consumption in heavy drinking mice as well as its efficacy in reducing alcohol‐induced hyperalgesia. These findings provide a foundation for the development of novel treatments for AUD and associated pain states.

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.

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.