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ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity

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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.

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Authors and Affiliations

  1. Neuroscience Discovery, Bldg. AP9A-LL (D-47W), Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, 60064-3500, Abbott Park, IL, USA

    Jorge D. Brioni, David J. B. Kim, Michael W. Decker & Stephen P. Arneric

  2. Department of Physiology and Biophysics (M/C 901), University of Illinois at Chicago, 901 S. Wolcott 202 MSB, 60612-7342, Chicago, IL, USA

    Mark S. Brodie

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  1. Jorge D. Brioni
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  2. David J. B. Kim
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  3. Mark S. Brodie
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  4. Michael W. Decker
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  5. Stephen P. Arneric
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Brioni, J.D., Kim, D.J.B., Brodie, M.S. et al. ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity. Psychopharmacology 119, 368–375 (1995). https://doi.org/10.1007/BF02245851

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  • DOI: https://doi.org/10.1007/BF02245851

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