β1-adrenergic receptors mediate plasma acyl-ghrelin elevation and depressive-like behavior induced by chronic psychosocial stress

Abstract

The ghrelin system is a key component of the mood and metabolic responses to chronic psychosocial stress. For example, circulating acyl-ghrelin rises in several rodent and human stress models, administered acyl-ghrelin induces antidepressant-like behavioral responses in mice, and mice with deleted ghrelin receptors (GHSRs) exhibit exaggerated depressive-like behaviors, changed eating behaviors, and altered metabolism in response to chronic stress. However, the mechanisms mediating stressinduced rises in ghrelin are unknown and ghrelin's antidepressant-like efficacy in the setting of chronic stress is incompletely characterized. Here, we used a pharmacological approach in combination with a 10-day chronic social defeat stress (CSDS) model in male mice to investigate whether the sympathoadrenal system is involved in the ghrelin response to stress. We also examined the antidepressant-like efficacy of administered ghrelin and the synthetic GHSR agonist GHRP-2 during and/or after CSDS. We found that administration of the β1-adrenergic receptor (β1AR) blocker atenolol during CSDS blunts the elevation of plasma acyl-ghrelin and exaggerates depressive-like behavior. Neither acute injection of acyl-ghrelin directly following CSDS nor its chronic administration during or after CSDS nor chronic delivery of GHRP-2 during and after CSDS improved stress-induced depressive-like behavior. Thus, β1ARs drive the acyl-ghrelin response to CSDS, but supplementing the natural increases in acyl-ghrelin with exogenous acyl-ghrelin or GHSR agonist does not further enhance the antidepressant-like actions of the endogenous ghrelin system in the setting of CSDS.

Ghrelin Protects Against Insulin-Induced Hypoglycemia in a Mouse Model of Type 1 Diabetes Mellitus

“…Notably, ghrelin induces cfos expression and increases CRF expression in hypothalamic CRF neurons, induces CRF release from hypothalamic explants, and increases plasma ACTH and epinephrine in rodent and/or human subjects (58)(59)(60)(61)(62)(63). Also relevant, epinephrine and norepinephrine are both potent ghrelin secretagogues, acting via ghrelin cell-expressed β 1 -adrenergic receptors to stimulate ghrelin secretion (30,64). As mentioned, mice with ghrelin cell-selective deletion of β 1 -adrenergic receptors exhibit marked hypoglycemia when exposed to a week-long, severe caloric restriction regimen (30).…”

The Good, the Bad and the Unknown Aspects of Ghrelin in Stress Coping and Stress-Related Psychiatric Disorders

“…A recent study demonstrated that intra-hippocampal administration of ghrelin fully and intraperitoneal injection partly normalized stressenhanced anxiety-and depression-like phenotypes in a CSDS paradigm (Han et al, 2019). However, another study found that reduced social interaction following CSDS exposure could not be rescued by subcutaneous administration of AG or ghrelin agonist GHRP-2 (Gupta et al, 2019).…”

“…On the other hand, chronic immobilization stress increased plasma AG levels in adrenalectomized rats (Meyer et al, 2014), indicating that stress can drive AG release independently of glucocorticoid production. Interestingly, a recent study demonstrated that elevated AG levels following chronic stress exposure could be reversed by the beta receptor antagonist atenolol (Gupta et al, 2019). This hydrophilic beta receptor antagonist does not readily cross the blood-brain barrier, suggesting that stress-induced elevations in plasma AG may be secondary to activation of the sympathetic nervous system.…”

The Ghrelin/Growth Hormone Secretagogue Receptor System Is Involved in the Rapid and Sustained Antidepressant-Like Effect of Paeoniflorin

“…Studies have shown that ghrelin-producing cells express high levels of β1 adrenergic receptors (β1-ARs). Genetic deletion of β1ARs in ghrelin-producing cells or the application of atenolol, a β1-AR-specific antagonist, decreased the plasma levels of both ghrelin and total ghrelin ( Mani et al, 2016 ; Gupta et al, 2019 ), suggesting that the sympathoadrenal system is involved in the regulation of ghrelin production. Meanwhile, it has also been reported that PF might act on peripheral β1-ARs ( Ohta et al, 1993 ).…”

“…In addition, exposure to CSDS elicited more severe depressive-like phenotypes in Ghsr -null ( Ghsr –/ – ) mice or hippocampal-specific GHSR1α knockdown mice than in their respective control littermates ( Lutter et al, 2008 ; Han et al, 2019 ). However, some studies have shown that chronic subcutaneous administration of ghrelin and growth hormone-releasing peptide 2, a synthesized agonist of GHSR1α, could not reverse the depressive-like behaviors induced by CSDS ( Gupta et al, 2019 ). Meanwhile, in male rats, the central administration of ghrelin induced depressive-like behaviors during the FST and tail suspension test ( Hansson et al, 2011 ; Jackson et al, 2019 ).…”