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The Journal of Neuroscience, August 6, 2003, 23(18):7155-7159

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BRIEF COMMUNICATION
Substance P Acts through Local Circuits within the Rat Dorsal Raphe Nucleus to Alter Serotonergic Neuronal Activity

Rita J. Valentino, Vincent Bey, Luise Pernar, and Kathryn G. Commons

The Children's Hospital of Philadelphia, Abramson Pediatric Research Center, Philadelphia, Pennsylvania 19104

Basic and clinical studies suggest that neurokinin 1 (NK1) receptor antagonists have efficacy in the treatment of affective disorders through effects on the dorsal raphe nucleus (DR), a source of forebrain-projecting serotonin (5-HT) neurons that has also been implicated in affective disorders. To investigate the regulation of the DR-5-HT system by NK1 receptors, the effects of substance P (an NK1 agonist) on rat DR neuronal activity were characterized. Most of the DR neurons (83%; n = 47 total) were inhibited by substance P microinfusion into the DR, and in some cases (17%) this was preceded by a brief activation. Pure excitation was observed in a small population of neurons (17%) that were localized in the dorsal DR, where NK1 receptors are most dense. Sendide, a selective NK1 antagonist, attenuated the effects of substance P, indicating that they were mediated by NK1 receptor activation. The selective 5-HT_1A antagonist, WAY 100635, administered systemically or into the DR, prevented the inhibitory effects of substance P, implicating DR 5-HT_1A receptors in this response. Finally, microinfusion of the excitatory amino acid antagonist, kynurenic acid, into the DR prevented both excitatory and inhibitory effects. The results suggest that NK1 receptor activation in the DR excites a population of 5-HT neurons via glutamatergic transmission. This results in 5-HT release throughout the DR, activation of 5-HT_1A receptors, and subsequent inhibition. Interactions between NK1 and 5-HT_1A receptors within DR neural networks may contribute to the mechanism of action of novel antidepressants acting at NK1 receptors.

Key words: serotonin; neurokinin 1; anxiety; glutamate; substance P; dorsal raphe nucleus; sendide

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Received Dec. 20, 2002; revised Jun. 10, 2003; accepted Jun. 16, 2003.

This article has been cited by other articles:

				B. P. Guiard, J.-P. Guilloux, C. Reperant, S. P. Hunt, M. Toth, and A. M. Gardier Substance P Neurokinin 1 Receptor Activation within the Dorsal Raphe Nucleus Controls Serotonin Release in the Mouse Frontal Cortex Mol. Pharmacol., December 1, 2007; 72(6): 1411 - 1418. [Abstract] [Full Text] [PDF]

				E. E. Nattie, A. Li, G. Richerson, and D. A. Lappi Medullary serotonergic neurones and adjacent neurones that express neurokinin-1 receptors are both involved in chemoreception in vivo J. Physiol., April 1, 2004; 556(1): 235 - 253. [Abstract] [Full Text] [PDF]

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