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J. Biol. Chem., Vol. 281, Issue 18, 12941-12949, May 5, 2006

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Chronic Antidepressants Potentiate via Sigma-1 Receptors the Brain-derived Neurotrophic Factor-induced Signaling for Glutamate Release^*

Yuki Yagasaki, Tadahiro Numakawa¹, Emi Kumamaru, Teruo Hayashi, Tsung-Ping Su, and Hiroshi Kunugi

From the Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo 187-8502, Japan and the Cellular Pathobiology Unit/DPS, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, Department of Health and Human Services, Baltimore, Maryland 21224

Up-regulation of BDNF (brain-derived neurotrophic factor) has been suggested to contribute to the action of antidepressants. However, it is unclear whether chronic treatment with antidepressants may influence acute BDNF signaling in central nervous system neurons. Because BDNF has been shown by us to reinforce excitatory glutamatergic transmission in cultured cortical neurons via the phospholipase- (PLC-)/inositol 1,4,5-trisphosphate (IP₃)/Ca²⁺ pathway (Numakawa, T., Yamagishi, S., Adachi, N., Matsumoto, T., Yokomaku, D., Yamada, M., and Hatanaka, H. (2002) J. Biol. Chem. 277, 6520-6529), we examined in this study the possible effects of pretreatment with antidepressants on the BDNF signaling through the PLC-)/IP₃/Ca²⁺ pathway. Furthermore, because the PLC-/IP₃/Ca²⁺ pathway is regulated by sigma-1 receptors (Hayashi, T., and Su, T. P. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 491-496), we examined whether the BDNF signaling is modulated by sigma-1 receptors (Sig-1R). We found that the BDNF-stimulated PLC- activation and the ensued increase in intracellular Ca²⁺ ([Ca²⁺]_i) were potentiated by pretreatment with imipramine or fluvoxamine, so was the BDNF-induced glutamate release. Furthermore, enhancement of the interaction between PLC- and TrkB (receptor for BDNF) after imipramine pretreatment was observed. Interestingly, BD1047, a potent Sig-1R antagonist, blocked the imipramine-dependent potentiation on the BDNF-induced PLC- activation and glutamate release. In contrast, overexpression of Sig-1R per se, without antidepressant pretreatment, enhances BDNF-induced PLC- activation and glutamate release. These results suggest that antidepressant pretreatment selectively enhance the BDNF signaling on the PLC-/IP₃/Ca²⁺ pathway via Sig-1R, and that Sig-1R plays an important role in BDNF signaling leading to glutamate release.

Received for publication, July 26, 2005 , and in revised form, January 20, 2006.

^* This work was supported by Research Grants 15A-1 and 16A-1 for Nervous and Mental Disorders from the Ministry of Health, Labor and Welfare (to H. K.), grants from the Mitsubishi Pharma Research Foundation (to H. K.), the Japan Foundation for Neuroscience and Mental Health (to H. K.), and the Japan Foundation for Aging and Health (to H. K. and T. N). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S2.

¹ To whom correspondence should be addressed. Tel.: 81-42-341-2711 (ext. 5132); Fax: 81-42-346-1744; E-mail: numakawa{at}ncnp.go.jp.

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