PT - JOURNAL ARTICLE AU - Katsura Tottori AU - Masami Nakai AU - Yasufumi Uwahodo AU - Takashi Miwa AU - Sakiko Yamada AU - Yasuo Oshiro AU - Tetsuro Kikuchi AU - C. Anthony Altar TI - Attenuation of Scopolamine-Induced and Age-Associated Memory Impairments by the Sigma and 5-Hydroxytryptamine<sub>1A</sub> Receptor Agonist OPC-14523 (1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-5-methoxy-3,4-dihydro-2[1<em>H</em>]-quinolinone monomethanesulfonate) AID - 10.1124/jpet.301.1.249 DP - 2002 Apr 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 249--257 VI - 301 IP - 1 4099 - http://jpet.aspetjournals.org/content/301/1/249.short 4100 - http://jpet.aspetjournals.org/content/301/1/249.full SO - J Pharmacol Exp Ther2002 Apr 01; 301 AB - Sigma and 5-HT1A 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-HT1Areceptor 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 μM 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-HT1A receptors. Combined sigma/5-HT1A receptor agonism may be a novel approach to ameliorate cognitive disorders associated with age-associated cholinergic deficits. The American Society for Pharmacology and Experimental Therapeutics