Selective reduction of alcohol drinking in Sardinian alcohol-preferring rats by a sigma-1 receptor antagonist.
OBJECTIVE
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.


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.


RESULTS
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.


CONCLUSIONS
The results implicate the Sig-1R system in alcohol drinking, identifying a potential therapeutic target for the treatment of alcohol use disorders.
Laboratory of Addictive Disorders, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118, USA. vsabino@bu.edu
Valentina
V
Sabino
Pietro
P
Cottone
Yu
Y
Zhao
Luca
L
Steardo
George F
GF
Koob
Eric P
EP
Zorrilla
D000428:Alcohol Drinking / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004326:Drinking / Q000187:drug effects*; D000431:Ethanol / Q000008:administration & dosage / Q000097:blood; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D013395:Sucrose / Q000008:administration & dosage; D013997:Time Factors; D000097605:Sigma-1 Receptor
D000840:Anisoles; D014150:Antipsychotic Agents; D002492:Central Nervous System Depressants; D000431:Ethanol; D011437:Propylamines; D017480:Receptors, sigma; D013395:Sucrose; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride