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

In the present study, we aimed to investigate the role of N-methylD- aspartate (NMDA) receptors in the antidepressant-like effects of a sigma(1) 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 sigma(1) 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] cyclohepten5,10- imine maleate (MK- 801). The present study indicated for the first time that the sigma(1) 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.