Earlier work has suggested that the sigma-1 receptor (Sig-1R) may be a viable target for the treatment of drug and alcohol addiction. We have shown previously that Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking. On the other hand, Sig-1R antagonists block excessive drinking in both genetic and environmental models of alcoholism, without affecting intake in outbred non-dependent rats. Even though significant progress has been made in understanding the function of Sig-1Rs in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. In 1992, we introduced the selective, high-affinity Sig 1R antagonist BD 1063 that has now become a valuable research tool. Administration of BD-1063 dramatically reduced the acquisition of alcohol drinking behavior as well as the preference for alcohol in genetically selected TSRI Sardinian alcohol preferring (Scr:sP) rats; the treatment had no effect on total fluid intake, food intake or body weight gain, proving selectivity of action. Furthermore, BD-1063 dose-dependently decreased alcohol-seeking behavior in rats trained under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a conditioned reinforcer. Finally, an innate elevation in Sig-1R protein levels was found in the nucleus accumbens of alcohol-preferring Scr:sP rats, compared to outbred Wistar rats, alteration which was normalized by chronic, voluntary alcohol drinking. Taken together our findings indicate that Sig-1R blockade reduce the propensity to both acquire alcohol drinking and to seek alcohol, and point as the nucleus accumbens as a potential key region for the effects observed. Our data suggest that Sig-1R antagonists may have therapeutic potential in multiple stages of alcohol addiction.
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