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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Ayanwuyi, Lydia O; Stopponi, Serena; Ubaldi, Massimo et al. (2015) Neurokinin 1 receptor blockade in the medial amygdala attenuates alcohol drinking in rats with innate anxiety but not in Wistar rats. Br J Pharmacol 172:5136-46
Schank, J R; Nelson, B S; Damadzic, R et al. (2015) Neurokinin-1 receptor antagonism attenuates neuronal activity triggered by stress-induced reinstatement of alcohol seeking. Neuropharmacology 99:106-14
Blasio, Angelo; Valenza, Marta; Iyer, Malliga R et al. (2015) Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats. Behav Brain Res 287:315-22
Corrigan, Frances; Wu, Yue; Tuke, Jonathan et al. (2015) Alcohol-induced sedation and synergistic interactions between alcohol and morphine: a key mechanistic role for Toll-like receptors and MyD88-dependent signaling. Brain Behav Immun 45:245-52
Schank, Jesse R; King, Courtney E; Sun, Hui et al. (2014) The role of the neurokinin-1 receptor in stress-induced reinstatement of alcohol and cocaine seeking. Neuropsychopharmacology 39:1093-101
Augier, E; Flanigan, M; Dulman, R S et al. (2014) Wistar rats acquire and maintain self-administration of 20 % ethanol without water deprivation, saccharin/sucrose fading, or extended access training. Psychopharmacology (Berl) 231:4561-8
Bajo, Michal; Madamba, Samuel G; Roberto, Marisa et al. (2014) Innate immune factors modulate ethanol interaction with GABAergic transmission in mouse central amygdala. Brain Behav Immun 40:191-202
Sabino, Valentina; Kwak, Jina; Rice, Kenner C et al. (2013) Pharmacological characterization of the 20% alcohol intermittent access model in Sardinian alcohol-preferring rats: a model of binge-like drinking. Alcohol Clin Exp Res 37:635-43
Schank, Jesse R; Tapocik, Jenica D; Barbier, Estelle et al. (2013) Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats. Biol Psychiatry 73:774-81
Lewis, Susannah S; Hutchinson, Mark R; Zhang, Yingning et al. (2013) Glucuronic acid and the ethanol metabolite ethyl-glucuronide cause toll-like receptor 4 activation and enhanced pain. Brain Behav Immun 30:24-32

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