Selective reduction of alcohol drinking in Sardinian alcohol-preferring rats by a sigma-1 receptor antagonist
- 1.7k Downloads
Rationale and objectives
Sigma receptors have been implicated in appetitive effects of psychostimulants and in high levels of ethanol intake. This study tested the hypothesis that the sigma-1 receptor subtype (Sig-1R) may modulate ethanol intake.
Material and methods
The effects of acute and repeated treatment with the potent, selective Sig-1R antagonist NE-100 on ethanol intake (10%) were studied in adult, male Sardinian alcohol-preferring (sP) rats, a model of genetic predisposition to high ethanol drinking. To assess the specificity of action, the acute effects of NE-100 on intake of an equally preferred sucrose solution and of a higher concentration of ethanol that sP rats did not prefer over water (28%), were determined. Finally, the ability of NE-100 administration to prevent the increased ethanol intake that occurs after deprivation was evaluated.
Acute treatment with NE-100 dose-dependently (10–30 mg/kg) reduced 1- and 3-h intake of 10% ethanol solution in sP rats, while increasing concurrent water intake and not affecting food intake. NE-100 (17.8–30 mg/kg) comparably reduced intake of the 28% ethanol solution, while not suppressing 1.25% sucrose solution intake, suggesting selectivity of action against ethanol intake. Acute NE-100 (30 mg/kg) also prevented an increase in ethanol intake after a 7-day deprivation period. Repeated, daily NE-100 (30 mg/kg) treatment continued to reduce 24-h ethanol intake across 7 days of administration, with some, but incomplete, tolerance, evident by day 6.
The results implicate the Sig-1R system in alcohol drinking, identifying a potential therapeutic target for the treatment of alcohol use disorders.
KeywordsEthanol Addiction Rat Alcoholism Treatment
Research was supported by grants from the National Institute on Alcohol Abuse and Alcoholism (5K99AA016731-02, 2P60AA006420-25, and 5R01AA012602-09) and by the Pearson Center for Alcoholism and Addiction Research. This is manuscript number 19878 from The Scripps Research Institute. The authors thank Taisho Pharmaceuticals for the gift of NE-100, the excellent technical assistance of Maury Cole, Molly Brennan, Jeanette Helfers and Robert Lintz, and the editorial assistance of Mike Arends.
Disclosure/conflicts of interest
The authors declare no conflicts of interest.
- Berardi F, Ferorelli S, Colabufo NA, Leopoldo M, Perrone R, Tortorella V (2001) A multireceptorial binding reinvestigation on an extended class of sigma ligands: N-[omega-(indan-1-yl and tetralin-1-yl) alkyl] derivatives of 3,3-dimethylpiperidine reveal high affinities towards sigma1 and EBP sites. Bioorg Med Chem 9:1325–1335PubMedCrossRefGoogle Scholar
- Nuwayhid SJ, Werling LL (2006) Sigma(2) (sigma(2)) receptors as a target for cocaine action in the rat striatum. Eur J PharmacolGoogle Scholar