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  • 1
    Electronic Resource
    Electronic Resource
    Evidence for Nicotinic Receptors Potentially Modulating Nociceptive Transmission at the Level of the Primary Sensory Neuron: Studies with F11 Cells (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 69 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: F11 cells are a dorsal root ganglion (DRG) cell line used to model the function of authentic type C, peptidergic, nociceptive neurons. The cellular events underlying the antinociceptive effects of (±)-epibatidine, a nicotinic acetylcholine receptor (nAChR) ligand that is 200-fold more potent than morphine, is unknown. The present study investigated the ability of cholinergic channel activators (ChCAs) to effect nAChR-gated ion flux and modulate the release of substance P (SP), a neuropeptide identified to play a critical role in nociception. The prototypical agonists (−)-nicotine and (−)-cytisine, the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium, the novel ChCA ABT-418 [(S)-3-methyl-5-(-1-methyl-2-pyrrolidinyl)isoxazole], and (±)-epibatidine evoked a concentration-dependent stimulation of rubidium (86Rb+) efflux with EC50 values of 14.2 ± 1.6, 63.4 ± 24, 3.8 ± 2.0, 29.8 ± 2.6, and 0.019 ± 0.001 µM as well as maximal intrinsic activities of 100, 97, 69, 75, and 102%, respectively. The noncompetitive nAChR antagonist mecamylamine potently antagonized (−)-nicotine-evoked ion flux, whereas the competitive antagonist dihydro-β-erythroidine was a weak antagonist, giving support to an α3β4 nAChR subtype. In addition, concentrations of (±)-epibatidine, similar to those necessary to induce maximal 86Rb+ efflux, evoked spontaneous release of SP from these cells, which was blocked by mecamylamine. Furthermore, prolonged exposure to (±)-epibatidine desensitized the functional response of the nAChR in this cell line (IC50 = 12 ± 9 nM). These findings in F11 cells provide a model to investigate the role nAChRs play in modulating DRG cell function, and may lead to insights into the role these receptors have in modulating nociceptive transmission.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69030930.x
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  • 2
    Electronic Resource
    Electronic Resource
    Preclinical Pharmacology of ABT-418: A Prototypical Cholinergic Channel Activator for the Potential Treatment of Alzheimer's Disease (1995)
    Oxford, UK : Blackwell Publishing Ltd
    CNS drug reviews 1 (1995), S. 0 
    Details
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3458.1995.tb00274.x
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity (1995)
    Springer
    Psychopharmacology 119 (1995), S. 368-375 
    Details
    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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  • 4
    Electronic Resource
    Electronic Resource
    Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418 (1997)
    Springer
    Psychopharmacology 130 (1997), S. 276-284 
    Details
    ISSN: 1432-2072
    Keywords: Key words Cognition ; Nicotine ; Delayed recall ; Monkeys ; Aging ; Transdermal ; Memory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2–259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized ”best dose” was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40–60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050240
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  • 5
    Electronic Resource
    Electronic Resource
    Central nicotinic receptor agonists ABT-418, ABT-089, and (–)-nicotine reduce distractibility in adult monkeys (1998)
    Springer
    Psychopharmacology 136 (1998), S. 50-58 
    Details
    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
    URL: http://dx.doi.org/10.1007/s002130050538
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