The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress

Abstract

We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic- and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin levels, whereas growth hormone secretagogue receptor (Ghsr) null mice showed increased deleterious effects of chronic defeat. Together, these findings demonstrate a previously unknown function for ghrelin in defending against depressive-like symptoms of chronic stress.

Figure 1

Anxiolytic- and antidepressant-like effects of ghrelin signaling. (a–d) Calorie restriction (CR) induced an anxiolytic-like effect in the EPM (*P < 0.02, a) and an antidepressant-like effect in the FST in wild-type, but not Ghsr^−/−, mice (latency to immobility, *P < 0.002; total immobility, *P < 0.02; c). Wild type ad lib indicates wild-type mice fed ad libitum. Administration of ghrelin (2 µg per g of body weight subcutaneously), but not saline, produced an anxiolytic-like effect in the EPM (*P < 0.05; b) and an antidepressant-like effect in the FST in wild-type mice 45 min after injection (latency to immobility, *P < 0.04; total immobility, *P < 0.0002; d). (e) The ghrelin-induced antidepressant-like effect that we observed in wild-type mice in the FST was absent in orexin-deficient (Hcrt^−/−) mice (n = 5 for both wild-type groups, n = 6 for the saline-treated Hcrt^−/− group, n = 7 for the ghrelin-treated Hcrt^−/− group). (f) Food intake responses of Ghsr^−/− and wild-type littermates following subcutaneous administration of ghrelin (2 µg per g) or saline in a crossover fashion at 10–11 weeks of age and again 1 month later. Statistically significant differences between food intake of ghrelin-injected wild-type mice and that of similarly treated Ghsr^−/− littermates and littermates treated with saline are indicated (*P < 0.001, n = 6 per group). Data are mean ± s.e.m. See Supplementary Methods online for detailed methods.

Figure 2

Ghrelin signaling regulates social isolation after CSDS. (a) Acylated ghrelin was persistently elevated after CSDS in wild-type C57BL6/J mice (significant effect of treatment, *P < 0.02; post hoc analysis showed no significant effect of day in the control mice; n = 5 in the control group and 10 in the CSDS group). (c) Ghsr^−/− mice showed increased social avoidance after CSDS (*P < 0.05). (b,d) Although there is no effect on body weight in any group either during or shortly after CSDS (b), increased food intake was induced during the 10 d of CSDS and maintained for at least 3 d following CSDS in wild-type, but not Ghsr^−/−, mice (during CSDS (days 1–10), *P < 0.002; after CSDS (days 11–13), *P < 0.002; n = 6 in each control group, 9 in the wild-type defeated group and 10 in the Ghsr^−/− defeated group; d). Data are mean ± s.e.m.