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.
Sabino
Valentina
V
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
Cottone
Pietro
P
Zhao
Yu
Y
Steardo
Luca
L
Koob
George F
GF
Zorrilla
Eric P
EP
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