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

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.

Hemokinin-1 Gene Expression Is Upregulated in Trigeminal Ganglia in an Inflammatory Orofacial Pain Model: Potential Role in Peripheral Sensitization

“…We have previously used the technique in NMRI mice [109], but in our experience C57Bl/6 mice tolerated this type of restraint less compared to the light manual handling. Changes in spontaneous behavior measured in the open field test corroborated previous results of our group regarding the possible role of HK-1 in mediating anxiolytic actions [40], but we could not detect any pain-induced reduction of spontaneous activity either (Supplementary Figure S1b).…”

“…However, several lines of evidence point to a different mechanism of action compared to SP, and even a yet unknown target. This is supported by the observations that the phenotype of Tac4 -/deficient mice in chronic pain models is different from SP or NK-1 receptor-deficient mice and an opposite phenotype was also described in models of anxiety and depression as well [40].…”

“…Although a few studies reported antibody development (e.g., [38]) or a recent immunohistochemical study on the TG with an in-house developed antibody [39], there are still no commercially available antibodies against HK-1. Despite the structural similarities and common receptors of HK-1 and SP, some of their functions appear to be different, even opposing each other [36,[40][41][42][43]. This could be explained by different binding sites and different signalling pathways by HK-1 compared to SP even at the NK-1 receptor, but a specific target is suggested to mediate several actions of HK-1 [36].…”

Beneficial effects of running exercise on hippocampal microglia and neuroinflammation in chronic unpredictable stress-induced depression model rats

“…The SPT was carried out as previously described [ 42 ]. Before the experiment, the rats were acclimated to the sucrose solution (1%, w/v).…”

Mouse Hemokinin-1 Decapeptide Subjected to a Brain-specific Post-translational Modification

“…inhibition or induction of pruritus) when administered in rats, through the activation of the NK1 receptor (18). Recent evidence showed anxiolytic and anti-depressant-like actions for mHK-1 (19). The nociceptive behaviors induced by mHK-1 were inhibited by NMDA receptor antagonists.…”