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.
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 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 micro mol/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 micro mol/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.
Guiard
Bruno P
BP
Laboratoire de Neuropharmacologie EA 3544 MJENR, Faculté de Pharmacie IFR75 - Institut de Signalisation et d'Innovation Thérapeutique, Université Paris-Sud, Châtenay-Malabry, France.
Przybylski
Cédric
C
Guilloux
Jean-Philippe
JP
Seif
Isabelle
I
Froger
Nicolas
N
De Felipe
Carmen
C
Hunt
Stephen P
SP
Lanfumey
Laurence
L
Gardier
Alain M
AM
D000818:Animals; D004333:Drug Administration Routes; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D064729:Neurokinin-1 Receptor Antagonists; D017374:Paroxetine / Q000494:pharmacology; D010477:Perfusion; D010880:Piperidines / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*
D064729:Neurokinin-1 Receptor Antagonists; D017374:Paroxetine; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013777:Tetrazoles; C103207:vofopitant