Blockade of substance P (neurokinin 1) receptors enhances extracellular serotonin when combined with a selective serotonin reuptake inhibitor: an in vivo microdialysis study in mice Bruno P. Guiard,* Ce ´dric Przybylski,* Jean-Philippe Guilloux,* Isabelle Seif,* Nicolas Froger,  Carmen De Felipe,à Stephen P. Hunt,§ Laurence Lanfumey and Alain M. Gardier* *Laboratoire de Neuropharmacologie EA 3544 MJENR, Faculte ´ de Pharmacie IFR75 – Institut de Signalisation et d’Innovation The ´rapeutique, Universite ´ Paris-Sud, Cha ˆtenay-Malabry, France  INSERM U288, CHU Pitie ´-Salpe ˆtrie `re, Paris, France àInstituto de Neurociencias, University Miguel Hernandez, Alicante, Spain §Department of Anatomy and Developmental Biology, University College, London, UK Abstract Substance P antagonists of the neurokinin-1 receptor type (NK1) are gaining growing interest as new antidepressant therapies. It has been postulated that these drugs exert this putative therapeutic effect without direct interactions with serotonin (5-HT) neurones. Our recent microdialysis experi- ment performed in NK1 receptor knockout mice suggested evidence of changes in 5-HT neuronal function (Froger et al. 2001). The aim of the present study was to evaluate the effects of coadministration of the selective 5-HT reuptake inhibitor (SSRI) paroxetine with a NK1 receptor antagonist (GR205171 or L733060), given either intraperitoneally (i.p.) or locally into the dorsal raphe nucleus, on extracellular levels of 5-HT ([5-HT]ext) in the frontal cortex and the dorsal raphe nucleus using in vivo microdialysis in awake, freely moving mice. The systemic or intraraphe administration of a NK1 receptor ant- agonist did not change basal cortical [5-HT]ext in mice. A single systemic dose of paroxetine (4 mg/kg; i.p.) resulted in a sta- tistically significant increase in [5-HT]ext with a larger extent in the dorsal raphe nucleus (+ 138% over basal AUC values), than in the frontal cortex (+ 52% over basal AUC values). Co-administration of paroxetine (4 mg/kg; i.p.) with the NK1 receptor antagonists, GR205171 (30 mg/kg; i.p.) or L733060 (40 mg/kg; i.p.), potentiated the effects of paroxetine on corti- cal [5-HT]ext in wild-type mice, whereas GR205171 (30 mg/kg; i.p.) had no effect on paroxetine-induced increase in cortical [5-HT]ext in NK1 receptor knock-out mice. When GR205171 (300 lmol/L) was perfused by ‘reverse microdialysis’ into the dorsal raphe nucleus, it potentiated the effects of paroxetine on cortical [5-HT]ext, and inhibited paroxetine-induced increase in [5-HT]ext in the dorsal raphe nucleus. Finally, in mice whose 5-HT transporters were first blocked by a local perfusion of 1 lmol/L of citalopram into the frontal cortex, a single dose of paroxetine (4 mg/kg i.p.) decreased cortical 5-HT release, and GR205171 (30 mg/kg i.p.) reversed this effect. The present findings suggest that NK1 receptor antagonists, when com- bined with a SSRI, augment 5-HT release by modulating substance P/5–HT interactions in the dorsal raphe nucleus. Keywords: depression, frontal cortex, intracerebral microdi- alysis, NK1 receptor antagonist, selective serotonin reuptake inhibitor, substance P. J. Neurochem. (2004) 89, 54–63. The clinical efficacy of antidepressant drugs such as selective serotonin re-uptake inhibitors (SSRIs) is based on facilitation of central serotonergic neurotransmission subsequent to the selective blockade of the serotonin (5-hydroxytryptamine, 5-HT) transporter. SSRIs are attractive drugs because they produce fewer adverse-effects than the first class of antide- pressants, the tricyclics. However, SSRIs have in common with all other antidepressant drugs several drawbacks such as the length of delay to achieve clinical benefits in depressed Received April 9, 2003; revised manuscript received November 19, 2003; accepted November 24, 2003. Address correspondence and reprint requests to Alain M. Gardier, Laboratoire de Neuropharmacologie Tour D1, 2e `me e ´tage, EA 3544 MJENR, Faculte ´ de Pharmacie, Universite ´ Paris-Sud, 5 rue J-B. Cle ´ment, 92296 Cha ˆtenay-Malabry cedex, France. E-mail: alain.gardier@cep.u-psud.fr Abbreviations used: AUC, area under the curve; 5-HT, serotonin; NK, neurokinin; NA, noradrenaline; SSRI, selective serotonin reuptake inhibitor. Journal of Neurochemistry , 2004, 89, 54–63 doi:10.1046/j.1471-4159.2003.02304.x 54 Ó 2004 International Society for Neurochemistry, J. Neurochem. (2004) 89, 54–63