Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys

Abstract

ABT-594 and A-582941 are high affinity neuronal nicotinic acetylcholine receptor agonists with differential selectivity for the alpha4beta2 and the alpha7 subtypes, respectively. This study was designed to determine whether either compound, like nicotine also possesses cognitive-enhancing ability. The compounds were administered by intramuscular injection to young adult Rhesus monkeys trained to perform two versions of a computer-assisted delayed matching-to-sample (DMTS) task. ABT-594 (0.115-3.7 microg/kg) significantly improved DMTS accuracies, shifting the retention curve (accuracy-delay relationship) to the right in a parallel fashion. DMTS accuracy also was maintained during the sessions initiated 24h after compound administration. Because task accuracy was improved during short delay trials, a separate study was performed in which non-predictable distractors were inserted within the DMTS format to impair accuracy. The 0.115 microg/kg dose of ABT-594 almost completely reversed distractor-impaired performance associated with short delay trials. The alpha7 nAChR agonist, A-582941 (1.14-38 microg/kg) also significantly improved DMTS accuracies. The compound produced a significant improvement during long delay trials. The effect was twice as robust for long delay as compared with short delay trials and A-582941 was not as effective as ABT-594 in improving short delay trial accuracy. A-582941 also failed to sustain task improvement during sessions run 24h after dosing. These data are consistent with the ability of subtype-preferring nicotinic receptor agonists to enhance specific components of working memory and cognitive function, and they suggest that differential subtype selectivity could result in varied pharmacological response profiles.