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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
Author(s) -
Guiard Bruno P.,
Przybylski Cédric,
Guilloux JeanPhilippe,
Seif Isabelle,
Froger Nicolas,
De Felipe Carmen,
Hunt Stephen P.,
Lanfumey Laurence,
Gardier Alain M.
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2003.02304.x
Subject(s) - microdialysis , serotonin , substance p , in vivo , pharmacology , reuptake inhibitor , serotonin reuptake inhibitor , chemistry , blockade , tachykinin receptor 1 , receptor , extracellular , 5 ht receptor , reuptake , serotonin uptake inhibitors , serotonin transporter , medicine , endocrinology , biology , neuropeptide , biochemistry , fluoxetine , microbiology and biotechnology
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 experiment 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 antagonist did not change basal cortical [5‐HT]ext in mice. A single systemic dose of paroxetine (4 mg/kg; i.p.) resulted in a statistically 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 cortical [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 µmol/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 µmol/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 combined with a SSRI, augment 5‐HT release by modulating substance P/5–HT interactions in the dorsal raphe nucleus.