Role of N-methyl-D-aspartate receptors in antidepressant-like effects of σ1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3- phenylpropyl)piperazine dihydrochloride (SA-4503) in olfactory bulbectomized rats

Dayong Wang, Yukihiro Noda, Hiroko Tsunekawa, Yuan Zhou, Masayuki Miyazaki, Koji Senzaki, Atsumi Nitta, Toshitaka Nabeshima

研究成果: Article

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In the present study, we aimed to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the antidepressant-like effects of a σ1 receptor agonist, 1-(3,4-dimethoxyphenethyl)-4-(3- phenylpropyl) piperazine dihydrochloride (SA-4503), in the olfactory bulbectomized (OB) rat model of depression. A symptomatology-based behavioral investigation was made by reconstructing in OB rats the symptoms of depression, such as psychomotor agitation, loss of interest, and cognitive dysfunction, using a typical antidepressant, desipramine, as a positive control. Repeated treatment with SA-4503 ameliorated the behavioral deficits in OB rats resembling depression symptoms in the open-field test, sexual behavior test, and cued and contextual fear-conditioning test. SA-4503 displayed advantages over desipramine in the sexual behavior test. SA-4503 also reversed the decrease in the protein expression of NMDA receptor subunit (NR)1, but not NR2A or NR2B, in the prefrontal cortex, hippocampus, and amygdala of OB rats. The behavioral and neurochemical effects of SA-4503 were blocked by combined treatment with a specific σ1 receptor antagonist, N,N-dipropyl-2-(4-methoxy-3- (2-phenylethoxy)phenyl) ethylamine monohydrochloride (NE-100). Furthermore, the effects of SA-4503 on the performance of OB rats in the behavioral tests were abrogated by acute treatment with an NMDA receptor antagonist, (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801). The present study indicated for the first time that the σ1 receptor agonist SA-4503 may have effects on depressive symptoms such as agitation, loss of interest, and impaired cognition, which are mediated by NMDA receptors.

元の言語English
ページ(範囲)1305-1314
ページ数10
ジャーナルJournal of Pharmacology and Experimental Therapeutics
322
発行部数3
DOI
出版物ステータスPublished - 01-09-2007
外部発表Yes

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All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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