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Accelerated Communication

Substance P Neurokinin 1 Receptor Activation within the Dorsal Raphe Nucleus Controls Serotonin Release in the Mouse Frontal Cortex

Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France (B.P.G, J.P.G, C.R., A.M.G.); Department of Anatomy and Developmental Biology, University College London, London, United Kingdom (S.P.H.); and Department of Pharmacology, Weill Medical College of Cornell University, New York, New York (M.T.)

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 intraraphe injection of SP on extracellular 5-HT levels in the frontal cortex, ventral hippocampus, and DRN by using intracerebral microdialysis in conscious mice. Intraraphe SP injection dose dependently decreased cortical 5-HT release, whereas no effects were detected in the ventral hippocampus. Cortical effects were blocked by the selective NK1 receptor antagonist N-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]phenyl]methyl]-2-phenylpiperidin-3-amine (GR205171) and completely dampened in mice lacking NK1 receptors. Furthermore, genetic (in knockout 5-HT_1A^-/- mice) or pharmacological inactivation of 5-HT_1A autoreceptors blocked cortical responses to SP. Contrasting with its cortical effects, intraraphe SP injection increased 5-HT outflow in the DRN in wild-type mice; this effect was potentiated by a local perfusion of the selective 5-HT_1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY100635). Finally, SP-induced changes in frontal cortex and DRN dialysate 5-HT levels were blocked by the DRN perfusion of the -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate ionotropic receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). These data support the hypothesis that SP-induced over-activation of 5-HT_1A 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.

Received for publication July 17, 2007.

Accepted for publication September 21, 2007.

Address correspondence to: Alain M. Gardier, Univ Paris-Sud EA 3544, Fac. Pharmacie, Chatenay-Malabry cedex F92296, France. E-mail: alain.gardier{at}u-psud.fr