Effects of memantine and donepezil on amyloid beta-induced memory impairment in a delayed-matching to position task in rats.
We investigated the effects of memantine and donepezil on amyloid beta (Abeta)-induced memory impairment in rats, which was assessed by a delayed-matching to position (DMPT) paradigm in three-lever operant chambers. Aggregated Abeta1-40 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 Abeta. Donepezil (2.5 mg/kg, p.o.) was administered 60 min before the DMTP test session. Bilateral microinjections of Abeta1-40 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 Abeta-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 Abeta-induced short-term memory impairment.
Yamada
Kiyofumi
K
Laboratory of Neuropsychopharmacology, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Takayanagi
Masanori
M
Kamei
Hiroyuki
H
Nagai
Taku
T
Dohniwa
Misato
M
Kobayashi
Kana
K
Yoshida
Shigeru
S
Ohhara
Tatsuo
T
Takuma
Kazuhiro
K
Nabeshima
Toshitaka
T
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D000077265:Donepezil; D004333:Drug Administration Routes; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage*; D005508:Food Deprivation; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007189:Indans / Q000008:administration & dosage*; D008297:Male; D008559:Memantine / Q000008:administration & dosage*; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D010446:Peptide Fragments / Q000633:toxicity*; D010880:Piperidines / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D010446:Peptide Fragments; D010880:Piperidines; C078592:amyloid beta-protein (1-40); D000077265:Donepezil; D008559:Memantine