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First published on September 21, 2007; DOI: 10.1124/mol.107.040113

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Received for publication July 17, 2007.
Revised September 21, 2007.
Accepted for publication September 21, 2007.

Substance P neurokinin 1 receptor activation within the dorsal raphe nucleus controls serotonin release in the mouse frontal cortex

Bruno P GUIARD 1, Jean-Philippe Guilloux 2, Christelle Reperant 2, Stephen P Hunt 3, Miklos Toth 4, Alain M Gardier 2*

1 Univ. Paris-Sud- EA 3544, Fac. Pharmacie, Chatenay-Malabry cedex F-92296, FRANCE 2 Univ. Paris-Sud, EA 3544, Fac. Pharmacie, Chatenay-Malabry cedex F-92296, FRANCE 3 Deptartment of Anatomy and Developmental Biology, University College London, Gower street, WC1E6BT L 4 Department of Pharmacology, Weill Medical College of Cornell University, New York, New York, USA

* Address correspondence to: E-mail: alain.gardier{at}u-psud.fr

Abstract

Preclinical studies suggest that Substance P (SP) neurokinin 1 (NK1) receptor antagonists are efficient in the treatment of anxiety and depression. This therapeutic activity could be mediated via stimulation of serotonin (5-HT) neurons located in the dorsal raphe nucleus (DRN), which receive important SP-NK1 receptor immunoreactive innervations. The present study examined the effects of intra-raphe injection of SP on extracellular 5-HT levels in the frontal cortex, ventral hippocampus and DRN by using intracerebral microdialysis in conscious mice. Intra-raphe SP injection dose-dependently decreased cortical 5-HT release while no effects were detected in the ventral hippocampus. Cortical effects were blocked by the selective NK1 receptor antagonist GR205171, and completely dampened in mice lacking NK1 receptors. Furthermore, genetic (in knockout 5-HT1A -/- mice) or pharmacological inactivation of 5-HT1A autoreceptors blocked cortical responses to SP. Contrasting with its cortical effects, intra-raphe SP injection increased 5-HT outflow in the DRN in wild-type mice, this effect being potentiated by a local perfusion of the selective 5-HT1A antagonist, WAY100635. Finally, SP-induced changes in frontal cortex and DRN dialysate 5-HT levels were blocked by the DRN perfusion of the AMPA/kainate ionotropic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). These data support the hypothesis that SP-induced over-activation of 5-HT1A autoreceptors within the DRN limits cortical 5-HT release. A better knowledge of the complex relationship between tachykininergic, serotonergic and glutamatergic systems within the DRN might help better understand the pathophysiology and subsequent treatment of depression.


Key words: Serotonin, Neuropeptides, Tachykinin, Knockout, Anti-depressants




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