Pharmacological stress is required for the anti-alcohol effect of the α3β4*nAChR partial agonist AT-1001

NEUROPHARMACOLOGY

卷:93

Article

Cippitelli, Andrea¹  Brunori, Gloria¹  Gaiolini, Kelly A.¹  Zaveri, Nurulain T.²  Toll, Lawrence¹ 

[1] Torrey Pines Inst Mol Studies, Port St Lucie, FL 34987 USA

[2] Astraea Therapeut, Mountain View, CA USA

关键词: AT-1001;    nAChR;    Alcohol;    Nicotine;    Stress;    Reinstatement;   

DOI  :  10.1016/j.neuropharm.2015.02.005

来源: Elsevier

【 摘 要 】

Alcohol and nicotine are often taken together. The mechanisms underlying this frequent co-abuse are not well known. Genetic and pharmacological evidence suggests that the nicotinic acetylcholine receptors (nAChRs) containing the alpha 3 and beta 4 subunits play a role in alcohol as well as nicotine addiction. AT-1001 is a high affinity alpha 3 beta 4 nAChR partial agonist recently found to block nicotine self-administration and relapse-like behavior in rats. Here, to study the involvement of alpha 3 beta 4 nAChRs in the mechanisms that regulate alcohol abuse we evaluated the effects of AT-1001 on alcohol taking and seeking in Sprague -Dawley rats. AT-1001 reduced operant alcohol self-administration at the highest dose examined (3.0 mg/kg), an effect also observed for food self-administration. A dose of 1.5 mg/kg AT-1001, which had no effect on alcohol or food self-administration, essentially eliminated reinstatement of alcohol seeking induced by yohimbine (0.625 mg/kg) whereas, reinstatement induced by alcohol-associated cues was not altered, nor did AT-1001 induce reinstatement of extinguished self-administration on its own. Finally, AT-1001 showed an anxiolytic activity when measured in the presence or absence of yohimbine stress in the elevated plus maze paradigm. Together, these observations do not support a specific involvement of the alpha 3 beta 4 nAChR in mediating alcohol reward or cue-induced relapse to alcohol seeking but rather indicate that the alpha 3 beta 4 nAChR partial agonism may constitute an attractive approach for treating alcohol use disorders exacerbated by elevated stress response. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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