title: High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice.
abstract: Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5-30mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20-30mg/kg). Pretreatment with AT-1001 (1-10mg/kg) or AT-1012 (3-10mg/kg) blocked CPP induced by 5mg/kg cocaine, but not by 30mg/kg cocaine. Lower doses of AT-1001 (0.3-1mg/kg) and AT-1012 (1-3mg/kg) did not affect the increase in locomotor activity induced by 5 or 30mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30mg/kg cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective α3β4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction.
authors.affiliation: SRI International, 333 Ravenswood Avenue, Menlo Park, CA, United States.
authors.forename: Taline V
authors.initials: TV
authors.lastname: Khroyan
authors.affiliation: Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA, United States.
authors.forename: Dennis
authors.initials: D
authors.lastname: Yasuda
authors.affiliation: Torrey Pines Institute for Molecular Studies, Jupiter, FL, United States.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Toll
authors.affiliation: SRI International, 333 Ravenswood Avenue, Menlo Park, CA, United States.
authors.forename: Willma E
authors.initials: WE
authors.lastname: Polgar
authors.affiliation: Astraea Therapeutics, 320 Logue Avenue, Mountain View, CA, United States. Electronic address: nurulain@astraeatherapeutics.com.
authors.forename: Nurulain T
authors.initials: NT
authors.lastname: Zaveri
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014326:Tropanes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000604695:AT-1012; D000814:Aniline Compounds; D018722:Nicotinic Agonists; D009842:Oligopeptides; D011978:Receptors, Nicotinic; D014326:Tropanes; C403530:nicotinic receptor alpha3beta4; C525167:larazotide acetate; D003042:Cocaine
keywords: Cocaine addiction; Cocaine-induced behavior; Cocaine-induced conditioned place preference; α3β4 nAChR-selective ligands; α3β4 nAChRs