br Conflicts of interest br Acknowledgments This work was su

Conflicts of interest
Acknowledgments This work was supported by the following funds: National Natural Science Foundation of China (81502222); Natural Science Foundation of Hubei Province (2013CFB370); Training program for Wuhan young and middle-aged medical backbone personnel (2017–51).
Introduction Depression is a severe affective disorder with substantial morbidity and high suicide rate [1]. Discoveries and evidences available are not sufficient to clarify the complicated physiopathology of such a mood disorder. Current clinical antidepressants are developed mainly based on the chemical imbalance of monoamines. However, the limited efficacy and the serious adverse effects of currently available antidepressants, remains a major concern [2]. Recently, neuropeptides were demonstrated to be essential to the depression-like behaviors [3], [4], which indicated a novel direction for the development of anti-depression therapy. Ghrelin, which crosses the blood–brain barrier and functions as a neuropeptide in the central nervous system, was initially identified in a rat stomach [5]. Ghrelin exert its functional activity in an acylated form by ghrelin O-acyltransferase (GOAT) enzyme [6]. Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor (GHSR) [7]. GHSR is highly distributed in hypothalamus, an important region that controls energy homeostasis and neuroendocrine functions [8], [9]. Nevertheless, a high GHSR expression is also found in extra-hypothalamic rp gift card australia regions such as hippocampus, ventral tegmental area (VTA) and amygdala [10], [11], [12], which are important sites of mood regulation. Growing evidence from preclinical and clinical studies suggest that the ghrelinergic system is involved in the physiopathology of depression [13]. Nakashima et al. found that Ghrl (Ghrelin and obestatin prepropeptide) gene exon region Leu72Met polymorphism was closely related to depression, but not to panic disorder [14]. However, the clinical studies about the serum ghrelin levels in depression patients were confusing, where it could be elevated [15], decreased [16] or even unchanged [17]. The main limitation may be that they could not demonstrate the basic ghrelin concentration levels before drug treatment. In animal studies, Lutter et al. found that subcutaneous injections of ghrelin or calorie restriction, produced antidepressant- and anxiolytic-like effect on chronic social defeat (CSD) mice, as well as GHSR-null mice showed a stronger depression-like symptom [18]. Another study reported that an acute i.c.v. administration of ghrelin can reverse depression-like behaviors induced by bilateral olfactory bulbectomy in mice [19]. Astonishingly, little is known about the effects of long-term ghrelin on these behaviors under chronic stress, forming a key point where our study was initiated. Chronic unpredictable mild stress (CUMS) in rodents is a classic depression model that could mimic many of the necessary features of depression [20]. Here, we conducted chronic peripheral ghrelin treatment on CUMS models to examine the antidepressant-like action of ghrelin by using some behavioral tests. Furthermore, to investigate the role of endogenous ghrelin in the pathological condition of depression, plasma acylated ghrelin levels and gastral preproghrelin mRNA were measured after CUMS treatment. Considering the fact that hippocampus is an important region that closely related to depression, we chose hippocampus as a target in present study to examine how ghrelin and GHSR changes in this site contributes to the pathological condition of depression. Furthermore, GHSR agonist, GHRP-6, was intracerebroventricularly administered to assess whether central GHSR mediated the antidepressant-like effect of exogenous ghrelin treatment.
Materials and methods
Results
Discussion It has been established that chronic stress is a major factor in the formation of depression in humans. Chronic stress on animals is able to evoke behavioral changes resembling clinical symptoms, such as anhedonia, weight loss, and locomotor activity deficit. CUMS is one kind of classical depression models, and it has been widely adopted to antidepressant compounds screening [20]. It has been reported that 2-week chronic stress is enough to induce depression-like behavior [21]. In this study, seven stress factors were applied on mice for 8 weeks in order to mimic the major depressive disorder. At first, we confirmed that CUMS could induce anxiety-like behaviors, as indicated in the results of EPM and OFT experiments. In addition, a significant decrease in rearing counts in OFT was observed, as well as increased time of immobility in FST, which were both associated with behavioral despair.