Activation of σ-receptors induces binge-like drinking in Sardinian alcohol-preferring rats

Abstract

Sigma (σ) receptors have been implicated in the behavioral and motivational effects of alcohol and psychostimulants. Sigma receptor antagonists reduce the reinforcing effects of alcohol and excessive alcohol intake in both genetic (alcohol-preferring rats) and environmental (chronic alcohol-induced) models of alcoholism. The present study tested the hypothesis that pharmacological activation of σ-receptors facilitates ethanol reinforcement and induces excessive, binge-like ethanol intake. The effects of repeated subcutaneous treatment with the selective σ-receptor agonist 1,3-di-(2-tolyl)guanidine (DTG; 15 mg/kg, twice a day for 7 days) on operant ethanol (10%) self-administration were studied in Sardinian alcohol-preferring (sP) rats. To confirm that the effect of DTG was mediated by σ-receptors, the effects of pretreatment with the selective σ-receptor antagonist BD-1063 (7 mg/kg, subcutaneously) were determined. To assess the specificity of action, the effects of DTG on the self-administration of equally reinforcing solutions of saccharin or sucrose were also determined. Finally, gene expression of opioid receptors in brain areas implicated in ethanol reinforcement was analyzed in ethanol-naive sP rats treated acutely or repeatedly with DTG, because of the well-established role of the opioid system in alcohol reinforcement and addiction. Repeatedly administered DTG progressively and dramatically increased ethanol self-administration in sP rats and increased blood alcohol levels, which reached mean values close to 100 mg% in 1 h drinking sessions. Repeated DTG treatment also increased the rats' motivation to work for alcohol under a progressive-ratio schedule of reinforcement. BD-1063 prevented the effects of DTG, confirming that σ-receptors mediate the effects of DTG. Repeated DTG treatment also increased the self-administration of the non-drug reinforcers saccharin and sucrose. Naive sP rats repeatedly treated with DTG showed increased mRNA expression of μ- and δ-opioid receptors in the ventral tegmental area. These results suggest a key facilitatory role for σ-receptors in the reinforcing effects of alcohol and identify a potential mechanism that contributes to binge-like and excessive drinking.

Figure 1

Effect of repeated subcutaneous pretreatment (twice a day for 7 days) with the σ-receptor agonist DTG on alcohol self-administration on a fixed-ratio 1 schedule of reinforcement in sP rats during 60-min sessions (n=8/group). Data represent mean±SEM intake normalized for body weight. The inset shows the blood alcohol levels of the two groups during day 8 of DTG administration, 25 min into the self-administration session. ^*p<0.05, ^**p<0.01, ^***p<0.001 vs vehicle-treated group (Student's t test).

Figure 2

Effect of pretreatment with the selective σ-receptor antagonist BD-1063 (−15 min) on DTG-induced increase in alcohol self-administration on a fixed-ratio 1 schedule of reinforcement in sP rats (n=8/group). Data represent the cumulative (7 days) mean±SEM intake normalized for body weight. ^**p<0.01 vs vehicle-treated group, ^##p<0.01 vs DTG-treated group (Dunnett's test).

Figure 3

Effect of repeated subcutaneous pretreatment (twice a day for 7 days) with the σ-receptor agonist DTG on alcohol self-administration on breakpoint (left panel) and total responses (right panel) for alcohol in sP rats (n=7–8/group) tested under a progressive ratio schedule of reinforcement. Data represent mean±SEM. ^*p<0.05, ^**p<0.01 vs vehicle-treated group (Student's t test).

Figure 4

μ-, δ- and κ- opioid receptor mRNA expression in the ventral tegmental area (top panels) and in the NAcc (bottom panels) of ethanol-naive Sardinian alcohol-preferring (sP) rats treated with vehicle or acutely or chronically with DTG (n=8–9/group). Rats were killed 4–5 h after the last treatment. Data represent mean±SEM expressed as percent of the vehicle-treated group. ^*p<0.05 vs vehicle-treated rats (Dunnett's test).