ISSN:
1432-2072
Keywords:
ABT-418
;
Nicotine
;
Nicotinic acetylcholine receptors
;
Drug discrimination
;
Mecamylamine
;
Ventral tegmental area
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract 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 µmol/kg in 39 days, they were not able to discriminate 1.9 or 6.2 µmol/kg ABT-418 from a saline solution during 50 days of training. In rats trained to discriminate 1.9 µmol/kg (−)-nicotine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 µmol/kg, an effect completely blocked by the cholinergic channel blocker mecamylamine (15 µmol/kg, IP). However, in extensively trained rats, intraperitoneal or subcutaneous injections of ABT-418 induced 78–82% generalization at the 6.2 µmol/kg dose. The predominant metabolites of (−)-nicotine and ABT-418 (cotinine 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.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02245851
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