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 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.
Buccafusco
J J
JJ
Department of Pharmacology and Toxicology, Alzheimer's Research Center, Medical College of Georgia, Augusta, USA.
Jackson
W J
WJ
Terry
A V
AV
Marsh
K C
KC
Decker
M W
MW
Arneric
S P
SP
D000818:Animals; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007555:Isoxazoles / Q000493:pharmacokinetics* / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects*; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects*; D009538:Nicotine / Q000494:pharmacology; D011759:Pyrrolidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013647:Task Performance and Analysis; D013997:Time Factors
D014151:Anti-Anxiety Agents; D007555:Isoxazoles; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D009538:Nicotine