The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking

Abstract

Sigma-Receptors (SigRs) have been implicated in behavioral and appetitive effects of psychostimulants and may also modulate the motivating properties of ethanol. This study tested the hypothesis that SigRs modulate ethanol reinforcement and contribute to excessive ethanol intake. The effects of subcutaneous treatment with the potent, selective Sig-1R antagonist BD-1063 on operant ethanol self-administration were studied in two models of excessive drinking-Sardinian alcohol-preferring (sP) rats and acutely withdrawn ethanol-dependent Wistar rats-and compared to ethanol self-administration in nondependent Wistar controls. To assess the specificity of action, the effects of BD-1063 on self-administration of an equally reinforcing saccharin solution were determined in Wistar and sP rats. Gene expression of Sig-1R in reward-related brain areas implicated in ethanol reinforcement was compared between ethanol-naive sP and Wistar rats and withdrawn ethanol-dependent Wistar rats. BD-1063 dose dependently reduced ethanol self-administration in sP rats (3.3-11 mg/kg) and withdrawn, dependent Wistar rats (4-11 mg/kg) at doses that did not modify mean ethanol self-administration in nondependent Wistar controls. BD-1063 did not reduce concurrent water self-administration and did not comparably suppress saccharin self-administration, suggesting selectivity of action. BD-1063 also reduced the breakpoints of sP rats to work for ethanol under a progressive-ratio reinforcement schedule. Ethanol-naive sP rats and 24-h withdrawn, dependent Wistar rats showed reduced Sig-1R mRNA expression in the nucleus accumbens. The results suggest that SigR systems may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence.

Fig. 1

Effect of acute subcutaneous pretreatment (-15 min) with the sigma receptor (SigR) antagonist BD-1063 on ethanol (panels A and B) and water (panels C and D) self-administration on a fixed ratio-1 schedule of reinforcement. Subjects were ethanol-dependent Wistar rats (n = 9), tested 6-hr into withdrawal from ethanol vapor, and non-dependent Wistar rats (n = 11). Data represent mean ± SEM intake, normalized for body weight (panels A and C), or number of lever press responses (panels B and D). * p < 0.05, ** p < 0.01 vs. vehicle-treated group (Dunnett’s test).

Fig. 2

Effect of acute subcutaneous pretreatment (-15 min) with the sigma receptor (SigR) antagonist BD-1063 on saccharin (panel A) and water (panel B) self-administration on a fixed ratio-1 schedule of reinforcement in Wistar rats (n = 8). Data represent mean ± SEM number of lever press responses.

Fig. 3

Effect of acute subcutaneous pretreatment (-15 min) with the sigma receptor (SigR) antagonist BD-1063 on alcohol (panels A and B) and water (panels C and D) self-administration on a fixed ratio-1 schedule of reinforcement in sP rats (n = 9). Data represent mean ± SEM intake normalized for body weight (panels A and C), or number of lever press responses (panels B and D). * p < 0.05, ** p < 0.01 vs. vehicle-treated group (Dunnett’s test).

Fig. 4

Time-course of the reduction of cumulative ethanol intake resulting from subcutaneous pretreatment with BD-1063 in sP rats (n = 9). Graph shows the cumulative ethanol intake at 5, 10, 15, 30 and 60 minutes into the session of subjects shown in Fig. 3. Data represent mean ± SEM. b= dose of 4.4 mg/kg, c= dose of 7 mg/kg, d= dose of 11 mg/kg, significantly different from vehicle (Dunnett’s test).

Fig. 5

Effect of acute subcutaneous pretreatment (-15 min) with the sigma receptor (SigR) antagonist BD-1063 on saccharin (panel A) and water (panel B) self-administration on a fixed ratio-1 schedule of reinforcement in sP rats (n = 8). Data represent the mean ± SEM number of lever press responses.

Fig. 6

Effect of acute subcutaneous pretreatment (-15 min) with the sigma receptor (SigR) antagonist BD-1063 on break point (panel A) and total responses (panel B) for ethanol in sP rats (n = 11) tested under a progressive ratio schedule of reinforcement. Data represent mean ± SEM. ** p < 0.01 vs. vehicle-treated group (Dunnett’s test).

Fig. 7

Sig-1R mRNA expression in the nucleus accumbens of ethanol-naïve Sardinian alcohol-preferring (sP) rats, ethanol-naïve outbred Wistar control rats, and acutely withdrawn (6-hr) Wistar rats previously made ethanol-dependent via intermittent exposure to ethanol vapors for 6 weeks (left panel, n = 7, 9 and 7, respectively) and ethanol-naïve outbred Wistar control rats, and acutely withdrawn (24-hr) Wistar rats (n = 9 and 7, respectively). Data represent mean ± SEM expressed as percent of the control group. * p < 0.05 vs. outbred control rats (Student’s t- test).