AF102B, a novel M1 agonist, enhanced spatial learning in C57BL/10 mice with a long duration of action

Orally administered AF102B, a selective muscarinic M1 cholinergic agonist, improved spatial learning in C57BL/10 mice in the Morris water maze. In four experiments in which all drug-treated animals received only one single administration of AF102B, improvement of acquisition depended on two factors: pretreatment time (tp) and dose. When a standard tp of 1 h was used, AF102B exhibited a U-shaped dose-response curve that is characteristic of many nootropic agents: learning was significantly improved by dose levels ranging from 0.1 to 1 mg/kg p.o. When the tp was extended out to as long as 8 days, two new effects emerged: (a) 1 mg/kg, the dose that had been the peak active dose at 1 h, exhibited a biphasic time course of action, being active at 1 h or at all tp intervals from 3 h to 5 days, but not at 1.5 h; (b) 0.03 mg/kg, a dose that had been inactive at a tp of 1 h, was active at all tp intervals from 3 h to 5 days, but not at shorter (1 and 2 h) or longer (6-8 days) tp intervals. In another experiment, animals received 0.03 mg/kg for 1-5 consecutive days: this dose level was active if the tp interval between the last dose and the learning session was 24-120 h, but not if it was only 1 h. Thus AF102B enhanced cognition in mice with a longer duration of action than reported for traditional muscarinic agonists.