Sustained pharmacological blockade of NK1 substance P receptors causes functional desensitization of dorsal raphe 5-HT 1A autoreceptors in mice.
Antagonists at NK1 substance P receptors have demonstrated similar antidepressant properties in both animal paradigms and in human as selective serotonin reuptake inhibitors (SSRIs) that induce desensitization of 5-HT 1A autoreceptors within the dorsal raphe nucleus (DRN). We investigated whether this receptor adaptation also occurs upon NK1 receptor blockade. C57B/L6J mice were treated for 21 days with the selective NK1 receptor antagonist GR 205171 (10 mg/kg daily) through subcutaneously implanted osmotic mini pumps, and DRN 5-HT 1A autoreceptor functioning was assessed using various approaches. Recording of DRN serotonergic neurons in brainstem slices showed that GR 205171 treatment reduced (by approximately 1.5 fold) the potency of the 5-HT 1A receptor agonist, ipsapirone, to inhibit cell firing. In parallel, the 5-HT 1A autoreceptor-mediated [35S]GTP-gamma-S binding induced by 5-carboxamidotryptamine onto the DRN in brainstem sections was significantly decreased in GR 205171-treated mice. In vivo microdialysis showed that the cortical 5-HT overflow caused by acute injection of the SSRI paroxetine (1 mg/kg) was twice as high in GR 205171-treated as in vehicle-treated controls. In the DRN, basal 5-HT outflow was significantly enhanced by GR 205171 treatment. These data supported the hypothesis that chronic NK1 receptor blockade induces a functional desensitization of 5-HT 1A autoreceptors similar to that observed with SSRIs.
Guiard
Bruno P
BP
INSERM/UPMC, Neuropsychopharmacologie, CHU Pitié-Salpêtrière, Paris, France.
Froger
Nicolas
N
Hamon
Michel
M
Gardier
Alain M
AM
Lanfumey
Laurence
L
D000818:Animals; D001345:Autoradiography; D017660:Autoreceptors / Q000187:drug effects*; D004594:Electrophysiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D064729:Neurokinin-1 Receptor Antagonists; D017374:Paroxetine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects*; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology
D017660:Autoreceptors; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D064729:Neurokinin-1 Receptor Antagonists; D017374:Paroxetine; D010880:Piperidines; D044282:Receptor, Serotonin, 5-HT1A; D018040:Receptors, Neurokinin-1; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D013777:Tetrazoles; C103207:vofopitant