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) KATSURA TOTTORI, MASAMI NAKAI, YASUFUMI UWAHODO, TAKASHI MIWA, SAKIKO YAMADA, YASUO OSHIRO, TETSURO KIKUCHI, AND C. ANTHONY ALTAR 1 Research Institute of Pharmacological and Therapeutical Development (K.T., Y.U., T.M., S.Y., T.K.), Second Institute of New Drug Discovery (M.N.), and Intellectual Property Department (Y.O.), Otsuka Pharmaceutical Co., Ltd., Tokushima, Japan; and Global Neuroscience Research (C.A.A.), Otsuka Maryland Research Institute, Rockville, Maryland Received October 29, 2001; accepted December 20, 2001 This article is available online at http://jpet.aspetjournals.org ABSTRACT 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 im- proved 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 acetylcholinester- ase (AChE) activity at concentrations up to 100 M and, unlike AChE inhibitors, did not cause peripheral cholinomimetic re- sponses. 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 im- proves scopolamine-induced and age-associated learning and memory impairments by enhancing ACh release, due to a stimu- lation 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. Acetylcholine (ACh) is a crucial mediator of learning and memory (Blokland, 1995). Drugs that reduce cholinergic function, such as the muscarinic receptor antagonist scopol- amine, cause profound memory impairments in animals and humans (Deutsch and Rocklin, 1967; Deutsch, 1971). The degeneration and dysfunction of cholinergic neurons is closely associated with the cognitive deficits of Alzheimer’s disease (Bartus et al., 1982; Coyle et al., 1983) and of aged rats and nonhuman primates (Gibson et al., 1981; Bartus et al., 1982). These findings provide a cholinomimetic rationale for treating Alzheimer’s disease (Becker, 1991) and support the use of animal models of learning impairments produced by age or muscarinic receptor antagonists (Yamazaki et al., 1995). Although early trials with ACh biosynthetic precursors failed to improve cognitive impairments associated with Alzheimer’s disease (Growdon, 1997), acetylcholinesterase (AChE) in- hibitors like tetrahydroaminoacridine (THA) and donepe- zil hydrochloride [()-2-[(1-benzylpiperidin-4-yl)methyl]-5, 6-dimethoxy-indan-1-one monohydrochloride] (E–2020) were found to improve experimental and clinical memory impair- ments (Smith et al., 1996; Jann, 2000). The varying success of these and other AChE inhibitors indicates that the augmenta- 1 Present address:Psychiatric Genomics, Inc. 19 Firstfield Road, Gaithers- burg, MD 20878. ABBREVIATIONS: ACh, acetylcholine; AChE, acetylcholinesterase; THA, tetrahydroaminoacridine; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; CAR, conditioned-avoidance response; CSF, cerebrospinal fluid; E-2020, ()-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride; IC 50 , 50% inhibitory concentration; NE-100, N,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)-phenyl]-ethylamine; ANOVA, analysis of variance; NMDA, N-methyl-D-aspartate; OPC-14523,1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-5-methoxy-3,4dihydro-2[1H]- quinolinone monomethanesulfonate. 0022-3565/02/3011-249 –257$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 301, No. 1 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 4693/972760 JPET 301:249–257, 2002 Printed in U.S.A. 249 at ASPET Journals on November 4, 2017 jpet.aspetjournals.org Downloaded from