Hemokinin-1 mediates anxiolytic and anti-depressant-like actions in mice.
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.
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.
Éva
É
Borbély
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.
Zsófia
Z
Hajna
King's College London, Institute of Pharmaceutical Science, London, UK.
Liza
L
Nabi
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.
Bálint
B
Scheich
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.
Valéria
V
Tékus
Department of Physiology, Medical School, University of Pécs, Hungary.
Kristóf
K
László
Department of Physiology, Medical School, University of Pécs, Hungary.
Tamás
T
Ollmann
Department of Anatomy, Medical School, University of Pécs, Hungary.
Viktória
V
Kormos
Department of Anatomy, Medical School, University of Pécs, Hungary.
Balázs
B
Gaszner
Department of Physiology, Medical School, University of Pécs, Hungary.
Zoltán
Z
Karádi
Department of Physiology, Medical School, University of Pécs, Hungary.
László
L
Lénárd
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Christopher J
CJ
Paige
Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine Liverpool University, Liverpool, UK.
John P
JP
Quinn
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.
János
J
Szolcsányi
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Hungary; János Szentágothai Research Centre, Centre for Neuroscience, University of Pécs, Hungary.
Erika
E
Pintér
King's College London, Institute of Pharmaceutical Science, London, UK.
Julie
J
Keeble
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Alexandra
A
Berger
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.
Zsuzsanna
Z
Helyes
D059445:Anhedonia; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000235:genetics* / Q000523:psychology; D003863:Depression / Q000235:genetics* / Q000523:psychology; D005518:Food Preferences; D016762:Genes, fos; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D011498:Protein Precursors / Q000235:genetics* / Q000502:physiology*; D018040:Receptors, Neurokinin-1 / Q000235:genetics; D013373:Substance P / Q000235:genetics; D015320:Tachykinins / Q000235:genetics* / Q000502:physiology*
D014151:Anti-Anxiety Agents; D011498:Protein Precursors; D018040:Receptors, Neurokinin-1; C423233:Tac4 protein, mouse; D015320:Tachykinins; D013373:Substance P
Behavior; Elevated plus maze test; Forced swim test; Fos immunohistochemistry; Light-dark box test; Open field test; Sucrose preference test; Tachykinins; Tail suspension test