Previous researches about ghrelin focused primarily on gastr

Previous researches about ghrelin focused primarily on gastrointestinal functions [30], energy balance [31], weight [32], and more recently on anxiety [33], [34], [35] and depression [36]. Here, we provided the first demonstration that chronic peripheral or central ghrelin treatment to CUMS rodents produced a significant antidepressant-like effect in the FST. These findings are in line with the reports that an acute i.c.v. administration of ghrelin can reverse depression-like behavior induced by bilateral olfactory bulbectomy in mice [19]. In another study, Lutter et al. found that acute subcutaneous injections of ghrelin or calorie restriction, produced anxiolytic- and antidepressant-like effect on CSD mice, as well as GHSR-null mice showed a stronger depression-like symptom [18]. Combing with our studies, central GHSR agonist treatment on CUMS rats ameliorated depression-like behaviors. We concluded that ghrelin can be the antidepressant target through binding with GHSR. Besides, suitable higher doses of ghrelin may drive strong feelings of hunger to compensate the anxiety-like behaviors. However, our studies contrasted with the research that 3 days administration of antisense DNA for ghrelin to rats exhibited antidepressant and anxiolytic effects [37] and anxiety-like effect after 28 days cerebroventricular administration of ghrelin [38]. There are other studies reported that microinjection of ghrelin into nucleus accumbens core enhances locomotor activity induced by cocaine [39] while administration into hypothalamus elicits anxiety-like behaviors [35]. Nonetheless, these studies were conducted on normal animals without stress. Ghrelin may play different role under physiologic or pathologic conditions. Region specificity and dosage of administration are other concerns that associated with this contradiction. Clinical studies delivered various results where the plasma ghrelin level in depressive patients has increased [15], decreased [16] or not changed [17]. One possible reason for this discordance is that they could not measure the basal levels of ghrelin in patients without medication. From this perspective, we first used the major depression model to test whether the plasma ghrelin has changed in mice under a prolong stress. Our results showed that the plasma ghrelin level was significantly elevated in mice after exposure to CUMS, consistent with previous animal studies that acute and sub-acute stress increased plasma ghrelin levels [40], [41]. Meanwhile, the number of ghrelin positive LY294002 and the transcript levels of Ghrl gene in stomach were both increased than that in normal group. These further demonstrated that peripheral ghrelin was elevated to cope with stress. Despite initial published reports of ghrelin-like immune reactivity in hypothalamus [42], [43], recent data showed that no evidence of ghrelin neurons in the brain by using ghrelin receptor reporter mice [44]. Surprisingly, we detected the mRNA level of preproghrelin, which encodes other proghrelin-derived peptides including ghrelin, was also increased in the hippocampus of CUMS group. In short, the activation of ghrelin in CUMS may be a homeostatic adaptation to deal with stress. In our studies, the CUMS group had a tendency to lose weight, but they increased more caloric intake than normal group. The elevation of ghrelin means to relieve the anxiety-like and depression-like symptoms at the expense of increased food. This may be the inherent neuromodulatory properties of ghrelin. Ghrelin stimulates growth hormone (GH) release by activating GHSR. GHSR is highly-expressed in hypothalamus and pituitary [8]. These regions are important for ghrelin to regulate energy metabolism. While high expression levels were also detected in hippocampus [10], [45], and the damage of hippocampus is closely related to mental disease. We observed the levels of GHSR mRNA and GHSR protein in hippocampus were both increased in CUMS mice. This may be due to the compensation of GHSR to adapt the elevation of ghrelin in order to exert its functional effect. Meanwhile, GHSR were located in the cell membrane of neurons in hippocampus as showed by immunofluorescence studies. Hippocampus is a brain region that involved in memory and mood regulation, and glutamate is the primary neurotransmitter. The glutamate receptors, such as NMDA, AMPA, kainite, and metabotropic receptors, are highly expressed in DG, CA1, CA2 [46], which are critical for Long-term potentiation (LTP) induction and synaptic plasticity [47]. Thus, ghrelin may play an indirect role to affect the synaptic plasticity, by influencing the release of glutamate or the expression of NMDA receptors, which are likely to be the consequence of GHSR activation [48]. Additional key elements to the plasticity in hippocampus are dopamine (DA) and their receptors, which also inherent to the reward circuits [49]. It is reported that glutamatergic and dopaminergic terminals are co-located in the same dendritic spines. Moreover, Andras Kern. Etc. demonstrated that hippocampus dopamine/DRD1 signaling is dependent on GHSR [50]. Thus, signaling through the GHSR modulates hippocampal function may also dependent on the cooperation with dopamine receptors.