title: Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function.
abstract: The present studies examined the role of norepinephrine (NE) system in mediating the enhancement of 5-HT function produced by neurokinin (NK)1 receptor antagonism. Dorsal raphe 5-HT and locus coeruleus NE neurons were recorded in vivo in mice lacking NK1 receptors in wildtype mice pretreated with the NK1 antagonist RP67580 and its inactive enantiomer RP 68651. RP67580 and RP68651 were also tested on 5-HT neurons of mice lacking the 5-HT(1A) receptor. RP67580 increased the firing rate of 5-HT neurons in wildtype mice and in 5-HT(1A) null mutant mice to the same degree, thus indicating that the mechanism by which NK1 antagonists enhances 5-HT firing is independent of 5-HT(1A) receptors. NE neuronal burst activity was increased in NK1 null mutant and wildtype mice given RP67580, but not with RP68651. After NE depletion, RP67580 was ineffective in increasing 5-HT neuronal firing activity in NK1 wildtype mice, and the enhancement of 5-HT neuronal firing observed in NK1 null mutant mice was abolished. In conclusion, NE neurons are essential for the action of NK1 antagonists on 5-HT neurons. In addition, the desensitization of 5-HT(1A) autoreceptors produced by NK1 receptor antagonism is not critical for enhancing 5-HT neuronal firing.
authors.affiliation: Department of Psychiatry, McGill University, 1033 Pine Avenue, West Montréal, QC, Canada H3A 1A1. Gabriella.Gobbi@McGill.ca
authors.forename: Gabriella
authors.initials: G
authors.lastname: Gobbi
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
authors.forename: Fatiha
authors.initials: F
authors.lastname: Radja
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Morgese
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cuomo
authors.forename: Luca
authors.initials: L
authors.lastname: Santarelli
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.forename: Pierre
authors.initials: P
authors.lastname: Blier
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000633:toxicity; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D008125:Locus Coeruleus / Q000166:cytology / Q000187:drug effects / Q000293:injuries; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D064729:Neurokinin-1 Receptor Antagonists; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000633:toxicity; D009638:Norepinephrine / Q000502:physiology*; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects / Q000293:injuries; D044282:Receptor, Serotonin, 5-HT1A / Q000172:deficiency; D018040:Receptors, Neurokinin-1 / Q000172:deficiency; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D001596:Benzylamines; D007211:Indoles; D054833:Isoindoles; D064729:Neurokinin-1 Receptor Antagonists; D009498:Neurotoxins; D018040:Receptors, Neurokinin-1; D044282:Receptor, Serotonin, 5-HT1A; C071693:7,7-diphenyl-2-(1-imino-2-(2-methoxyphenyl)ethyl)perhydroisoindol-4-one; D012701:Serotonin; C012102:DSP 4; D009638:Norepinephrine