Attenuation of scopolamine-induced and age-associated memory impairments by the sigma and 5-hydroxytryptamine(1A) receptor agonist OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethanesulfonate).
Sigma and 5-HT(1A) receptor stimulation can increase acetylcholine (ACh) release in the brain. Because ACh release facilitates learning and memory, we evaluated the degree to which OPC-14523 (1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2[1H]-quinolinone monomethane sulfonate), a novel sigma and 5-HT(1A) receptor agonist, can augment ACh release and improve learning impairments in rats due to cholinergic- or age-related deficits. Single oral administration of OPC-14523 improved scopolamine-induced learning impairments in the passive-avoidance task and memory impairment in the Morris water maze. The chronic oral administration of OPC-14523 attenuated age-associated impairments of learning acquisition in the water maze and in the conditioned active-avoidance response test. OPC-14523 did not alter basal locomotion or inhibit acetylcholinesterase (AChE) activity at concentrations up to 100 microM and, unlike AChE inhibitors, did not cause peripheral cholinomimetic responses. ACh release in the dorsal hippocampus of freely moving rats increased after oral delivery of OPC-14523 and after local delivery of OPC-14523 into the hippocampus. The increases in hippocampal ACh release were blocked by the sigma receptor antagonist NE-100 (N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine). Thus, OPC-14523 improves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimulation of sigma and probably 5-HT(1A) receptors. Combined sigma/5-HT(1A) receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits.
Tottori
Katsura
K
Research Institute of Pharmacological and Therapeutical Development, Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan. k_tottori@research.otsuka.co.jp
Nakai
Masami
M
Uwahodo
Yasufumi
Y
Miwa
Takashi
T
Yamada
Sakiko
S
Oshiro
Yasuo
Y
Kikuchi
Tetsuro
T
Altar
C Anthony
CA
D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000375:Aging / Q000187:drug effects / Q000523:psychology*; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D018678:Cholinergic Agents / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced* / Q000523:psychology; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma / Q000037:antagonists & inhibitors; D012601:Scopolamine / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
C404207:1-(3-(4-(3-chlorophenyl)-1-piperazinyl)propyl)-3,4-dihydro-5-methoxy-2(1H)-quinolinone; D000840:Anisoles; D018678:Cholinergic Agents; D002800:Cholinesterase Inhibitors; D018727:Muscarinic Antagonists; D010879:Piperazines; D011437:Propylamines; D015363:Quinolones; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma; D017366:Serotonin Receptor Agonists; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride; D012601:Scopolamine; D000110:Acetylcholinesterase; D000109:Acetylcholine