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J. J. Buccafusco W. J. Jackson A. V. Terry Jr K. C. Marsh M. W. Decker S. P. Arneric 《Psychopharmacology》1995,120(3):256-266
ABT-418, a newly characterized centrally acting cholinergic channel activator (ChCA), was evaluated for its ability to improve
performance in a delayed matching-to-sample (DMTS) task by mature macaques well trained in the task. Previous studies in rodents
have indicated that ABT-418 shares the memory/cognitive enhancing actions of nicotine, but without many of nicotine's dose-limiting
side effects. As DMTS provides a measure both of general cognitive function (the matching concept) and of recent memory, it
was hypothesized that some doses of ABT-418 would enhance the monkeys' ability to correctly perform the DMTS task. Intramuscular
administration of ABT-418 significantly enhanced DMTS performance at low (2–32.4 nmol/kg) doses. In fact, the drug was slightly
more potent that nicotine in this regard, and all eight animals tested in this study exhibited enhanced performance at one
or more doses. ABT-418 produced the greatest improvement in DMTS performance at the longest delay interval. In animals repeatedly
tested with their individualized “Best Dose”, DMTS performance increased on average by 10.1 ± 3.5 percentage points correct,
which was equivalent to an increase of 16.2% over baseline performance. ABT-418 did not significantly affect response times,
i.e., latencies to make a choice between stimuli, or latencies to initiate new trials. Whereas nicotine enhanced DMTS performance
both on the day of administration and on the following day (in the absence of drug), ABT-418-induced enhanced performance
was detected only on the day of administration. Finally, single daily administration of the individualized best dose in three
monkeys over a period of 8 days generally maintained enhancement of DMTS performance. Thus, the data were not consistent with
the development of significant tolerance to the drug's mnemonic actions. In contrast to nicotine, no overt toxicity or side
effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of
nicotinic agonists designed for the potential treatment of human dementias having a low profile of toxicity. 相似文献
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