ABT-418 - DISCRIMINATIVE STIMULUS PROPERTIES AND EFFECT ON VENTRAL TEGMENTAL CELL-ACTIVITY

Previous studies have established that ABT-418 [(S)-3-methyl-5-(1 meth yl-2-pyrrolidinyl)isoxazole hydrochloride] is a novel neuronal nicotin ic acetylcholine receptor (nAChR) ligand with cognitive enhancing and anxiolytic-like activity 3- to 10-fold more potent than (-)-nicotine i n rodents. A series of experiments was conducted to determine the disc riminative stimulus properties of ABT-418 in comparison with (-)-nicot ine, and to determine the relative potencies of these compounds on ven tral tegmental area (VTA) neurons. While rats were able to discriminat e(-)-nicotine 1.9 mu mol/kg in 39 days, they were not able to discrimi nate 1.9 or 6.2 mu mol/kg ABT-418 from a saline solution during 50 day s of training. In rats trained to discriminate 1.9 mu mol/kg (-)-nicot ine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 mu mol/kg, an effect completely blocked by the cholinergic channel block er mecamylamine (15 mu mol/kg, IF). However, in extensively trained ra ts, intraperitoneal or subcutaneous injections of ABT-418 induced 78-8 2% generalization at the 6.2 mu mol/kg dose. The predominant metabolit es of(-)-nicotine and ABT-418 (cotinine and A-87770, respectively) wer e devoid of any effect in nicotine-trained rats. The reduced potency o f ABT-418 in nicotine-trained rats is consistent with the electrophysi ological findings showing that ABT-418 is 3-fold less potent than (-)- nicotine in activating dopamine-containing neurons in the VTA area.