title: Pharmacological stress is required for the anti-alcohol effect of the α3β4* nAChR partial agonist AT-1001.
abstract: 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 α3 and β4 subunits play a role in alcohol as well as nicotine addiction. AT-1001 is a high affinity α3β4 nAChR partial agonist recently found to block nicotine self-administration and relapse-like behavior in rats. Here, to study the involvement of α3β4 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 α3β4 nAChR in mediating alcohol reward or cue-induced relapse to alcohol seeking but rather indicate that the α3β4 nAChR partial agonism may constitute an attractive approach for treating alcohol use disorders exacerbated by elevated stress response.
authors: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA. Electronic address: acippitelli@tpims.org.
authors: Andrea
authors: A
authors: Cippitelli
authors: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.
authors: Gloria
authors: G
authors: Brunori
authors: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.
authors: Kelly A
authors: KA
authors: Gaiolini
authors: Astraea Therapeutics, Mountain View, CA, USA.
authors: Nurulain T
authors: NT
authors: Zaveri
authors: Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL, USA.
authors: Lawrence
authors: L
authors: Toll
mesh_terms: D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D000437:Alcoholism / Q000188:drug therapy*; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003216:Conditioning, Operant; D003463:Cues; D004195:Disease Models, Animal; D054333:Drug Partial Agonism; D058999:Drug-Seeking Behavior / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D009842:Oligopeptides / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic; D012054:Reinforcement, Psychology; D012646:Self Administration; D015016:Yohimbine / Q000627:therapeutic use
chemical_list: D058669:Adrenergic alpha-2 Receptor Antagonists; D002492:Central Nervous System Depressants; D018722:Nicotinic Agonists; D009842:Oligopeptides; D011978:Receptors, Nicotinic; C403530:nicotinic receptor alpha3beta4; D015016:Yohimbine; D000431:Ethanol; C525167:larazotide acetate
keywords: AT-1001; Alcohol; Nicotine; Reinstatement; Stress; nAChR