Authors: Shigeyuki Chaki Toshiharu Shimazaki Junichi Karasawa Takeshi Aoki Ayaka Kaku Michihiko Iijima Daiji Kambe Shuji Yamamoto Yasunori Kawakita Tsuyoshi Shibata Kumi Abe Taketoshi Okubo Yoshinori Sekiguchi Shigeru Okuyama
Publish Date: 2015/04/15
Volume: 232, Issue: 15, Pages: 2849-2861
Abstract
Since the hypofunction of the NmethylDaspartate NMDA receptor is known to be involved in the pathophysiology of schizophrenia the enhancement of NMDA receptor function through glycine modulatory sites is expected to be a useful approach for the treatment of schizophreniaWe investigated the efficacy of a glycine transporter 1 GlyT1 inhibitor that potentiates NMDA receptor function by increasing synaptic glycine levels in animal models for cognitive dysfunction and negative symptoms both of which are poorly managed by current antipsychoticsA newly synthesized GlyT1 inhibitor 3chloroNS31ethyl1Hpyrazol4ylphenyl2Spiperidin2ylmethyl4trifluoromethylpyridine2carboxamide TASP0315003 significantly improved cognitive deficit induced by MK801 in the object recognition test in rats Likewise TASP0315003 significantly improved MK801 impaired cognition in the social recognition test in rats and also enhanced social memory in treatmentnaïve rats In addition repeated phencyclidine PCP treatment reduced the social interaction of paired mice which may reflect negative symptoms such as social withdrawal and both acute and subchronic treatment with TASP0315003 reversed the reduction in social interaction induced by PCP Moreover TASP0315003 additionally exhibited an antidepressant effect in the forced swimming test in rats In contrast TASP0315003 did not affect spontaneous locomotor activity or rotarod performance and did not induce catalepsy indicating that TASP0315003 does not cause sedation or motor dysfunction which is sometimes observed with the use of current antipsychotics
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