We have previously reported that
AC-3933, a newly developed
benzodiazepine receptor partial inverse agonist, facilitates
acetylcholine release in the hippocampus and ameliorates
scopolamine-induced
memory deficits in rats. To further confirm the procognitive effect of
AC-3933, we assessed in this study the beneficial effects of this compound in aged mice using the Y-maze and object recognition tests. In addition, we investigated the synergistic effect of
AC-3933 and
donepezil, a
cholinesterase inhibitor, on
scopolamine-induced memory impairment in mice. In aged mice,
oral administration of
AC-3933 at doses of 0.05-0.1 mg/kg and 0.05 mg/kg significantly improved spatial working memory and episodic memory, respectively. In
scopolamine-treated mice, both
AC-3933 and
donepezil significantly ameliorated
memory deficits in the Y-maze test at doses of 0.3-3 mg/kg and 10-15 mg/kg, respectively. The beneficial effect of
AC-3933, but not that of
donepezil, on
scopolamine-induced memory impairment was antagonized by
flumazenil, a
benzodiazepine receptor antagonist, indicating that the procognitive action of
AC-3933 arises via a mechanism different from that of
donepezil. Co-administration of
donepezil at the suboptimal dose of 3 mg/kg with
AC-3933 at doses of 0.1-1 mg/kg significantly ameliorated
scopolamine-induced memory impairment, suggesting that
AC-3933 potentiates the effect of
donepezil on memory impairment induced by
cholinergic hypofunction. These findings indicate that
AC-3933 not only has good potential as a
cognitive enhancer by itself, but also is useful as a concomitant
drug for the treatment of Alzheimer׳s disease.