We investigated the effects of memantine and donepezil on amyloid β (Aβ)-induced memory impairment in rats, which was assessed by a delayed-matching to position (DMPT) paradigm in three-lever operant chambers. Aggregated Aβ1-40 was microinjected bilaterally (1 nmol/side) into both CA1 and CA3 subfields of the hippocampus in rats that had previously performed the DMTP task. Memantine (20 mg/(kg day), s.c.) was continuously infused by an osmotic minipump for 4 weeks from 3 days before the microinjection of Aβ. Donepezil (2.5 mg/kg, p.o.) was administered 60 min before the DMTP test session. Bilateral microinjections of Aβ1-40 into the hippocampus resulted in a delayed, but persistent impairment of DMTP performance, which appeared more than 50 days after the injection. Memantine prevented the development of Aβ-induced memory impairment, while donepezil symptomatically alleviated the deficits. Because of a ceiling effect, the combination of donepezil with memantine failed to produce any additive or synergic effects. These results support the clinical data showing that memantine and donepezil are effective for the treatment of Alzheimer's disease. Moreover, it is suggested that memantine is effective for preventing Aβ-induced short-term memory impairment.
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