Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice.

Autor: Borbély É; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary., Hajna Z; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary., Nabi L; King's College London, Institute of Pharmaceutical Science, London, UK., Scheich B; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary., Tékus V; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary., László K; Department of Physiology, Medical School, University of Pécs, Hungary., Ollmann T; Department of Physiology, Medical School, University of Pécs, Hungary., Kormos V; Department of Anatomy, Medical School, University of Pécs, Hungary., Gaszner B; Department of Anatomy, Medical School, University of Pécs, Hungary., Karádi Z; Department of Physiology, Medical School, University of Pécs, Hungary., Lénárd L; Department of Physiology, Medical School, University of Pécs, Hungary., Paige CJ; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Quinn JP; Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine Liverpool University, Liverpool, UK., Szolcsányi J; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary., Pintér E; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary., Keeble J; King's College London, Institute of Pharmaceutical Science, London, UK., Berger A; Princess Margaret Cancer Centre, University Health Network, Toronto, Canada., Helyes Z; Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary; MTA-PTE NAP B Chronic Pain Research Group, Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.
Jazyk: angličtina
Zdroj: Brain, behavior, and immunity [Brain Behav Immun] 2017 Jan; Vol. 59, pp. 219-232. Date of Electronic Publication: 2016 Sep 09.
DOI: 10.1016/j.bbi.2016.09.004
Abstrakt: The tachykinin NK1 receptor was suggested to be involved in psychiatric disorders, but its antagonists have failed to be effective as antidepressants in clinical trials. Hemokinin-1 (HK-1), the newest tachykinin, is present in several brain regions and activates the NK1 receptor similarly to substance P (SP), but acts also through other mechanisms. Therefore, we investigated the roles of the Tac4 gene-derived HK-1 in comparison with SP and neurokinin A (NKA) encoded by the Tac1 gene, as well as the NK1 receptor in anxiety and depression-like behaviors in mice. Mice lacking SP/NKA, HK-1 or the NK1 receptor (Tac1 -/- , Tac4 -/- , Tacr1 -/- , respectively) compared to C57Bl/6 wildtypes (WT), and treatment with the NK1 antagonist CP99994 were used in the experiments. Anxiety was evaluated in the light-dark box (LDB) and the elevated plus maze (EPM), locomotor activity in the open field (OFT) tests. Hedonic behavior was assessed in the sucrose preference test (SPT), depression-like behavior in the tail suspension (TST) and forced swim (FST) tests. FST-induced neuronal responsiveness was evaluated with Fos immunohistochemistry in several stress-related brain regions. In the LDB, Tac4 -/- mice spent significantly less, while Tacr1 -/- and CP99994-treated mice spent significantly more time in the lit compartment. In the EPM only Tac4 -/- showed reduced time in the open arms, but no difference was observed in any other groups. In the OFT Tac4 -/- mice showed significantly reduced, while Tac1 -/- and Tacr1 -/- animals increased motility than the WTs, but CP99994 had no effect. NK1 -/- consumed markedly more, while Tac4 -/- less sucrose solution compared to WTs. In the TST and FST, Tac4 -/- mice showed significantly increased immobility. However, depression-like behavior was decreased both in cases of genetic deletion and pharmacological blockade of the NK1 receptor. FST-induced neuronal activation in different nuclei involved in behavioral and neuroendocrine stress responses was significantly reduced in the brain of Tac4 -/- mice. Our results provide the first evidence for an anxiolytic and anti-depressant-like actions of HK-1 through a presently unknown target-mediated mechanism. Identification of its receptor and/or signaling pathways might open new perspectives for anxiolytic and anti-depressant therapies.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: