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  • 1
    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
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  • 2
    ISSN: 1432-2072
    Keywords: Key words Cognition ; Distractibility ; ( ; )-Nicotine ; ABT-418 ; ABT-089 ; Monkey ; Delay matching
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Increased distractibility is associated with both Alzheimer’s disease and attention deficit disorder. The present study examined the effects of (–)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)- pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (IM) administration of (–)-nicotine, in doses of 5.4–43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0–16.2 nmol/kg, IM) and ABT-089 (16.4–32.8 nmol/kg, IM) prevented distractibility, producing increases of 7.5–25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (–)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.
    Type of Medium: Electronic Resource
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