A Study On Depression-like Effect Of Neuronostatin In Mice

Background Neuronostatin is a 13-amino acid peptide with C-terminal amidation that has been predicted based on bioinformatic analysis of evolutionarily conserved sequences in the pro-somatostatin protein. It is widely expressed in diverse neuronal, metabolic, and gastrointestinal tissues and plays important physiological roles in the regulation of neuroendocrine, cardiovascular and metabolic functions. Neuronostatin led to a biphasic, dose-related increase in mean arterial pressure, which seemed due to increase sympathetic nervous system activity and initiate vasopressin release from the posterior pituitary through the central melanocortin system.The central melanocortin system and vasopressin are both involved in emotional states such as anxiety and depression. In addition, neuronostatin has been detected in the hippocampus, the regions known to modulate emotion processing. Therefore, neuronostatin may have a potential activities in psychiatric disorders including depression. the putative role of neuronostatin in mood regulation have not been demonstrated up to now.Objective This study explored the effect of neuronostatin in the depression response, and whether the effect of neuronostatin is dose-, opioid system- or GABA system- dependent would be explored.Methods Neuronostatin and non-amidated neuronostatin were synthesized by manual solid-phase synthesis using standard Fmoc chemistry. The effects of neuronostatin and non-amidated neuronostatin on depression-like effect were investigated in mice in the forced swimming test. And then nonselective opioid receptor antagonist naloxone and GABAA receptor antagonist bicuculline were used to clarify mechanism of depression-like effect induced by neuronostatin. In addition, we examined that whether C-terminal amidation of neuronostatin is needed to its depressive activity. In order to eliminate a false positive response in the forced swim test that the increase of immobility time was due to locomotor suppression, the effect of neuronostatin on locomotor activity was examined.Results In the present study, we found that the i.c.v. administration of neuronostatin produced a dose-related increase in immobility time in the forced swim test (P<0.05), and non-amidated neuronostatin failed to alter immobility time (P>0.05). Neuronostatin had no effect on the locomotor activity in mice (P>0.05). In the antagonism studies, naloxone, an antagonist of opioid receptor, did not significantly alter the depression-like response induced by neuronostatin (P>0.05); while the GABAA receptor antagonist bicuculline significantly reversed the increase of immobility time induced by neuronostatin (P<0.01).Conclusion Our results first showed that central administration of neuronostatin induced depression-like effect in forced swim test. The effect was mediated, at least in part, by GABAA receptor. C-terminal amidation of neuronostatin is essential to exert its depressive effect. These findings revealed that neuronostatin may be related with major depressive disorder.