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ABSTRACT-YM992 ((S)-2-[[ (7-fluoroindan-4-yl)oxy]methyl]morpholine) monohydrochloride is a novel antidepressant with selective serotonin (5-hydroxytryptamine, 5-HT) re-uptake inhibition and 5-HT 2A receptor antagonistic activity. The effects of YM992 and two selective 5-HT re-uptake inhibitors (SSRIs) were studied in a marble-burying behavior test as a model of an obsessive-compulsive disorder (OCD) in mice at doses of 5, 10 and 15 mg /kg, i.p. YM992 and fluoxetine significantly inhibited marble-burying behavior at a dose of 15 mg /kg (i.p.) without affecting spontaneous locomotor activities. Citalopram also significantly inhibited the behavior at doses of 5, 10 and 15 mg /kg (i.p.) without affecting spontaneous locomotor activities. These results suggest that YM992, as well as SSRIs, may exhibit anti-OCD activity in addition to an antidepressive effect in clinical use.

This review focuses on the in vitro and in vivo neuropharmacology of YM872, a potential neuroprotective agent currently undergoing clinical trials in the United States (trial name: AMPA Receptor Antagonist Treatment in Ischemic Stroke -ARTIST). Its neuroprotective properties in rats and cats with induced focal cerebral ischemia are described. YM872, [2,3-dioxo-7-(1H-imidazol-1-yl)-6-nitro-1,2,3,4-tetrahydroquinoxalin-1-yl]-acetic acid monohydrate, is a selective, potent and highly water-soluble competitive á-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist. YM872 has a potent inhibitory effect on [ 3 H]AMPA binding with a K i value of 0.096 ìM. In contrast, YM872 has very low affinity for other ionotropic glutamate receptors. The solubility of YM872 is approximately 500 to 1000 times higher than that of the other competitive AMPA antagonists: YM90K, NBQX, or CNQX. The neuroprotective efficacy of YM872 was investigated in rats and cats subjected to permanent occlusion of the left middle cerebral artery. The animals were assessed either histologically or neurologically following ischemia. In rats with occluded middle cerebral artery (MCAO) YM872, by i.v. infusion, significantly reduced infarct volume measured at 24 h and 1 week after ischemia. Significant neuroprotection was maintained even when drug administration was delayed 337

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Abstract-We designed a new method for studying working memory, by using a repeated acquisition procedure in the three-panel runway apparatus. This ap paratus is composed of a start box, a goal box and four consecutive choice points; each choice point consists of three panel gates.Male Wistar rats were trained with 6 consecutive trials (one session) per day. Each trial was performed every two minutes.In this apparatus, rats could pass through only one gate (correct gate) among three panel gates in the direction of the goal box and were given 100 mg food pellets as the positive reinforcement.The sequence of correct gate position in each rat was changed everyday, but not in each session.Error responses (pushing the incorrect gate) were gradually reduced as training was repeated, and the learning was established within 16 training sessions to achieve criterion performance. Intraperitoneal scopolamine and intrahippocampal ethylcholine aziridinium ion (AF64A) produced increases in both the number of errors and the latency in a dose-dependent manner.The increase in errors induced by AF64A did not return to the control level, though the prolonged latency returned to normal. As a con clusion, this experimental procedure using the three-panel runway apparatus would be a useful method for studying working memory, and its memory deficit is involved at least in the dysfunction of the cholinergic system in the hippocampus.

Using a repeated acquisition procedure in a three-panel runway apparatus, the effects of minaprine on the impairment of working memory produced by scopolamine, ethylcholine aziridinium ion (AF64A) or cerebral ischemia were investigated in rats. Minaprine (3.2-32 mg/kg IP) as well as idebenone (10-100 mg/kg IP) and physostigmine (0.1-0.32 mg/kg IP) dose-dependently reduced the increase of errors (pushes made on the two incorrect panels located at each choice point) induced by 0.56 mg/kg IP scopolamine. Cerebral ischemia for 5 min caused a significant increase of errors in the runway task. Minaprine at 3.2 and 10 mg/kg administered IP immediately after blood recirculation and again 30 min before the runway test conducted 24 h after ischemia, significantly reduced increases in errors expected to occur after 5 min of ischemia. Physostigmine 0.1 mg/kg similarly attenuated the increase in errors in ischemic rats. However, minaprine at doses up to 32 mg/kg IP failed to reduce the increase of errors induced by AF64A 2.5 nmol injected into the dorsal hippocampus. These findings suggest that minaprine exerts an ameliorating effect on amnesia produced by scopolamine and cerebral ischemia, probably through mediation of its stimulant action on central cholinergic systems.