Peripherally Circulating Ghrelin Does Not Mediate Alcohol‐Induced Reward and Alcohol Intake in Rodents

Abstract

BackgroundDevelopment of alcohol dependence, a chronic and relapsing disease, largely depends on the effects of alcohol on the brain reward systems. By elucidating the mechanisms involved in alcohol use disorder, novel treatment strategies may be developed. Ghrelin, the endogenous ligand for the growth hormone secretagogue receptor 1A, acts as an important regulator of energy balance. Recently ghrelin and its receptor were shown to mediate alcohol reward and to control alcohol consumption in rodents. However, the role of central versus peripheral ghrelin for alcohol reward needs to be elucidated.MethodsGiven that ghrelin mainly is produced by peripheral organs, the present study was designed to investigate the role of circulating endogenous ghelin for alcohol reward and for alcohol intake in rodents.ResultsWe showed that the Spiegelmer NOX‐B11‐2, which binds and neutralizes acylated ghrelin in the periphery with high affinity and thus prevents its brain access, does not attenuate the alcohol‐induced locomotor activity, accumbal dopamine release and expression of conditioned place preference in mice. Moreover, NOX‐B11‐2 does not affect alcohol intake using the intermittent access 20% alcohol 2‐bottle‐choice drinking paradigm in rats, suggesting that circulating ghrelin does not regulate alcohol intake or the rewarding properties of alcohol. In the present study, we showed however, that NOX‐B11‐2 reduced food intake in rats supporting a role for circulating ghrelin as physiological regulators of food intake. Moreover, NOX‐B11‐2 did not affect the blood alcohol concentration in mice.ConclusionsCollectively, the past and present studies suggest that central, rather than peripheral, ghrelin signaling may be a potential target for pharmacological treatment of alcohol dependence.

Intermittent access to a nutritionally complete high-fat diet attenuates alcohol drinking in rats

“…Interestingly, rats in the HFD exposure group displayed significantly elevated basal levels of acyl-ghrelin (Figure 7b), the active form of ghrelin (Kirchner et al, 2009), even though they consumed less alcohol. In fact, this surprising finding is in agreement with a recent report, which indicates that activity of the central ghrelin receptor (GHSR) but not increases in circulating ghrelin, stimulates alcohol intake in rodents (Jerlhag et al, 2014). It is possible that decreased GHSR signaling may underlie the decreased alcohol intake observed following HFD exposure.…”

Ghrelin in psychiatric disorders – A review

“…This hypothesis is supported by the phenomenon of stress eating and the observation that ghrelin mediates stress-induced food-reward in mice (Chuang et al, 2011). Also, a strong overlap of neurobiological mechanisms regulating food and drug reward has been repeatedly hypothesized (Thiele et al, 2004;Morganstern et al, 2011;Jerlhag et al, 2014b) and results from animal and human studies involving ghrelin in food and drug reward, presented in the following, seem to lend further support to this hypothesis.…”

“…In support of this, a recent review suggests that ghrelin, via an interaction with dopamine signaling, alters the motivational state of an organism, increasing incentive to obtain food (Lockie and Andrews, 2013). This would explain ghrelin's involvement in addictive disorders, especially since food reward and drug reward seem to share common neurobiological pathways (Thiele et al, 2004;Morganstern et al, 2011;Jerlhag et al, 2014b). Beyond that, substantial evidence suggests that ghrelin might act as an intrinsic antidepressant agent, protecting from depressive-like symptoms in response to stress (Lutter et al, 2008;Walker et al, 2014) and consequently promoting behavior which ensures survival.…”

Growth hormone secretagogue receptor signalling affects high‐fat intake independently of plasma levels of ghrelin andLEAP2, in a 4‐day binge eating model

“…Of particular note, a recent study reported that ghrelin‐independent GHSR activity in the brain modulates cocaine‐induced reward in mice . Similarly, GHSR activity can affect alcohol‐induced reward and compulsive alcohol intake in rodents, independently of circulating ghrelin levels . Notably, a recent preliminary study reported that administration of the GHSR inverse agonist PF‐5190457 reduces alcohol and food craving in humans .…”