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NEUROPHARMACOLOGY

Role of N-Methyl-D-aspartate Receptors in Antidepressant-Like Effects of ₁ Receptor Agonist 1-(3,4-Dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine Dihydrochloride (SA-4503) in Olfactory Bulbectomized Rats

Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan (D.W., Y.N., H.T., Y.Z., M.M., K.S., A.N., T.N.); Division of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, Japan (Y.N.); Division of Scientific Affairs, Japanese Society of Pharmacopoeia, Tokyo, Japan (D.W.); Japanese Drug Organization of Appropriate Use and Research, Nagoya, Japan (T.N.); Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan (T.N.); and Research Institute, Fujimoto Pharmaceutical Corporation, Osaka, Japan (H.T.)

In the present study, we aimed to investigate the role of N-methyl-D-aspartate (NMDA) receptors in the antidepressant-like effects of a 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 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]cyclohepten-5,10-imine maleate (MK-801). The present study indicated for the first time that the 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.

Address correspondence to: Dr. Toshitaka Nabeshima, Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya 468-0069, Japan. E-mail: tnabeshi{at}ccmfs.meijo-u.ac.jp