ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity.
Previous studies have established that ABT-418 [(S)-3-methyl-5-(1 methyl-2-pyrrolidinyl)isoxazole hydrochloride] is a novel neuronal nicotinic acetylcholine receptor (nAChR) ligand with cognitive enhancing and anxiolytic-like activity 3- to 10-fold more potent than (-)-nicotine in rodents. A series of experiments was conducted to determine the discriminative stimulus properties of ABT-418 in comparison with (-)-nicotine, and to determine the relative potencies of these compounds on ventral tegmental area (VTA) neurons. While rats were able to discriminate (-)-nicotine 1.9 mumol/kg in 39 days, they were not able to discriminate 1.9 or 6.2 mumol/kg ABT-418 from a saline solution during 50 days of training. In rats trained to discriminate 1.9 mumol/kg (-)-nicotine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 mumol/kg, an effect completely blocked by the cholinergic channel blocker mecamylamine (15 mumol/kg, IP). However, in extensively trained rats, intraperitoneal or subcutaneous injections of ABT-418 induced 78-82% generalization at the 6.2 mumol/kg dose. The predominant metabolites of (-)-nicotine and ABT-418 (continine and A-87770, respectively) were devoid of any effect in nicotine-trained rats. The reduced potency of ABT-418 in nicotine-trained rats is consistent with the electrophysiological findings showing that ABT-418 is 3-fold less potent than (-)-nicotine in activating dopamine-containing neurons in the VTA area.
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal; D004192:Discrimination, Psychological; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009538:Nicotine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D017557:Ventral Tegmental Area / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D007555:Isoxazoles; D011759:Pyrrolidines; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D008464:Mecamylamine; D009538:Nicotine