title: Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats.
abstract: Sigma-1 receptor (Sig-1R) has been proposed as a novel therapeutic target for drug and alcohol addiction. We have shown previously that Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while Sig-1R antagonists on the other hand block excessive drinking in 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-1R in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. Administration of the selective Sig-1R antagonist 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 instead 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 these findings demonstrate that Sig-1R blockade reduces the propensity to both acquire alcohol drinking and to seek alcohol, and point to 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.
authors.affiliation: Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Angelo
authors.initials: A
authors.lastname: Blasio
authors.affiliation: Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Valenza
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Malliga R
authors.initials: MR
authors.lastname: Iyer
authors.affiliation: Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Department of Health and Human Services, Bethesda, MD, USA.
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.affiliation: Department of Physiology and Pharmacology Vittorio Erspamer, Sapienza University of Rome, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Steardo
authors.affiliation: Department of Medicine, Nishikawa Hospital, Hamada, Shimane, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.affiliation: Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Pietro
authors.initials: P
authors.lastname: Cottone
authors.affiliation: Laboratory of Addictive Disorders, Departments of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, MA, USA. Electronic address: vsabino@bu.edu.
authors.forename: Valentina
authors.initials: V
authors.lastname: Sabino
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy / Q000503:physiopathology*; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000378:metabolism; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol; D008297:Male; D009714:Nucleus Accumbens / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000097605:Sigma-1 Receptor
chemical_list: D000431:Ethanol; D010879:Piperazines; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine
keywords: Addiction; Ethanol; Intake; Rat; Reinforcement; Reward
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