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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)1305-1314
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume322
Issue number3
DOIs
Publication statusPublished - 01-09-2007
Externally publishedYes

Fingerprint

N-Methyl-D-Aspartate Receptors
Antidepressive Agents
Depression
Desipramine
Sexual Behavior
Psychomotor Agitation
Imines
Dizocilpine Maleate
SA 4503
Amygdala
Prefrontal Cortex
Cognition
Fear
Hippocampus
Behavior Rating Scale
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "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",
abstract = "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.",
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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. / Wang, Dayong; Noda, Yukihiro; Tsunekawa, Hiroko; Zhou, Yuan; Miyazaki, Masayuki; Senzaki, Koji; Nitta, Atsumi; Nabeshima, Toshitaka.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 322, No. 3, 01.09.2007, p. 1305-1314.

Research output: Contribution to journalArticle

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T1 - 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

AU - Wang, Dayong

AU - Noda, Yukihiro

AU - Tsunekawa, Hiroko

AU - Zhou, Yuan

AU - Miyazaki, Masayuki

AU - Senzaki, Koji

AU - Nitta, Atsumi

AU - Nabeshima, Toshitaka

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