title: Paradoxical response to the sedative effects of diazepam and alcohol in C57BL/6J mice lacking the neuropeptide S receptor.
abstract: The neuropeptide S (NPS) system is characterized by a unique pharmacology because it has anxiolytic-like effects and promotes arousal and wakefulness. To shed light on this peptidergic system, we tested the sedative effect of the central depressants diazepam and ethanol on the loss of righting reflex in mice lacking the neuropeptide S receptor (NPSR), NPSR(-/-). Furthermore, we tested the effect of the intracerebroventricular (ICV) administration of NPS on the sedative effect of diazepam and ethanol in NPSR(-/-) and their wild type counterpart NPSR(+/+). Finally, we evaluated the effect of the pro-arousal neuropeptides CRF and Hcrt-1/Ox-A in NPSR-deficient mice. Contrary to our expectations, the results showed that the NPSR(-/-) were less sensitive to the hypnotic effects of both diazepam and ethanol compared with their wild type littermates. ICV NPS was able to attenuate the sedative effect of both alcohol and diazepam in wild type mice, but not in the NPSR(-/-) line. The administration of CRF and Hcrt-1/Ox-A, two classic pro-arousal peptides, elicited the same effects in both NPSR(-/-) and wild type mice, ruling out the possibility that adaptive mechanisms occurring at the level of these two systems could have occurred during NPSR(-/-) development to compensate for the lack of NPSR receptors. Our findings demonstrated that the deletion of NPSR leads to minor changes in the arousal behavior of mice. Moreover, we demonstrated that the deletion of NPSR did not lead to compensatory changes in the vigilance-promoting effects of the CRF and Hcrt-1/Ox-A systems.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, MC, Italy.
authors.forename: Pasha
authors.initials: P
authors.lastname: Ghazal
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, 37135 Verona, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, 37135 Verona, Italy.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Roth
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, 37135 Verona, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Faggioni
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, 37135 Verona, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Corti
authors.affiliation: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Medicines Research Centre, 37135 Verona, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Merlo Pick
authors.affiliation: School of Biosciences and Biotechnology, University of Camerino, Via Madonna delle Carceri, 62032 Camerino, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pucciarelli
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, MC, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, MC, Italy. Electronic address: massimo.ubaldi@unicam.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Ubaldi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology*; D000431:Ethanol / Q000494:pharmacology*; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology; D000068797:Orexins; D018013:Receptors, Neuropeptide / Q000172:deficiency*
chemical_list: D002492:Central Nervous System Depressants; C000596233:Hcrt protein, mouse; D006993:Hypnotics and Sedatives; D009479:Neuropeptides; D000068797:Orexins; D018013:Receptors, Neuropeptide; C583532:neuropeptide S receptor, mouse; C539972:neuropeptide S, mouse; D000431:Ethanol; D003346:Corticotropin-Releasing Hormone; D003975:Diazepam
keywords: Alcohol; CRF; Hcrt-1/Ox-A; NPS; NPSR KO mice; Sedation