IMPROVEMENT IN PERFORMANCE OF A DELAYED MATCHING-TO-SAMPLE TASK BY MONKEYS FOLLOWING ABT-418 - A NOVEL CHOLINERGIC CHANNEL ACTIVATOR FOR MEMORY ENHANCEMENT

ABT-418, a newly characterized centrally acting cholinergic channel ac tivator (ChCA), was evaluated for its ability to improve performance i n a delayed matching-to-sample (DMTS) task by mature macaques well tra ined in the task. Previous studies in rodents have indicated that ABT- 418 shares the memory/cognitive enhancing actions of nicotine, but wit hout 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 woul d enhance the monkeys' ability to correctly perform the DMTS task. Int ramuscular administration of ABT-418 significantly enhanced DMTS perfo rmance at low (2-32.4 nmol/kg) doses. In fact, the drug was slightly m ore 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 long est delay interval. In animals repeatedly tested with their individual ized ''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 l atencies to initiate new trials. Whereas nicotine enhanced DMTS perfor mance both on the day of administration and on the following day (in t he absence of drug), ABT-418-induced enhanced performance was detected only on the day of administration. Finally, single daily administrati on 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 toleranc e to the drug's mnemonic actions. In contrast to nicotine, no overt to xicity or side effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of ni cotinic agonists designed for the potential treatment of human dementi as having a low profile of toxicity.