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Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice.
Brain Behav Immun 2017; 59:219-232BB

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.King's College London, Institute of Pharmaceutical Science, London, UK.Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.Department of Physiology, Medical School, University of Pécs, Hungary.Department of Physiology, Medical School, University of Pécs, Hungary.Department of Anatomy, Medical School, University of Pécs, Hungary.Department of Anatomy, Medical School, University of Pécs, Hungary.Department of Physiology, Medical School, University of Pécs, Hungary.Department of Physiology, Medical School, University of Pécs, Hungary.Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine Liverpool University, Liverpool, UK.Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.King's College London, Institute of Pharmaceutical Science, London, UK.Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27621226

Citation

Borbély, Éva, et al. "Hemokinin-1 Mediates Anxiolytic and Anti-depressant-like Actions in Mice." Brain, Behavior, and Immunity, vol. 59, 2017, pp. 219-232.
Borbély É, Hajna Z, Nabi L, et al. Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice. Brain Behav Immun. 2017;59:219-232.
Borbély, É., Hajna, Z., Nabi, L., Scheich, B., Tékus, V., László, K., ... Helyes, Z. (2017). Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice. Brain, Behavior, and Immunity, 59, pp. 219-232. doi:10.1016/j.bbi.2016.09.004.
Borbély É, et al. Hemokinin-1 Mediates Anxiolytic and Anti-depressant-like Actions in Mice. Brain Behav Immun. 2017;59:219-232. PubMed PMID: 27621226.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice. AU - Borbély,Éva, AU - Hajna,Zsófia, AU - Nabi,Liza, AU - Scheich,Bálint, AU - Tékus,Valéria, AU - László,Kristóf, AU - Ollmann,Tamás, AU - Kormos,Viktória, AU - Gaszner,Balázs, AU - Karádi,Zoltán, AU - Lénárd,László, AU - Paige,Christopher J, AU - Quinn,John P, AU - Szolcsányi,János, AU - Pintér,Erika, AU - Keeble,Julie, AU - Berger,Alexandra, AU - Helyes,Zsuzsanna, Y1 - 2016/09/09/ PY - 2016/06/13/received PY - 2016/08/25/revised PY - 2016/09/07/accepted PY - 2016/9/14/pubmed PY - 2018/8/24/medline PY - 2016/9/14/entrez KW - Behavior KW - Elevated plus maze test KW - Forced swim test KW - Fos immunohistochemistry KW - Light-dark box test KW - Open field test KW - Sucrose preference test KW - Tachykinins KW - Tail suspension test SP - 219 EP - 232 JF - Brain, behavior, and immunity JO - Brain Behav. Immun. VL - 59 N2 - 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. SN - 1090-2139 UR - https://www.unboundmedicine.com/medline/citation/27621226/Hemokinin_1_mediates_anxiolytic_and_anti_depressant_like_actions_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0889-1591(16)30413-5 DB - PRIME DP - Unbound Medicine ER -