Stress, Motivation, and the Gut-Brain Axis: A Focus on the Ghrelin System and Alcohol Use Disorder

Abstract

Since its discovery, the gut hormone, ghrelin, has been implicated in diverse functional roles in the central nervous system. Central and peripheral interactions between ghrelin and other hormones, including the stress-response hormone cortisol, govern complex behavioral responses to external cues and internal states. By acting at ventral tegmental area dopaminergic projections and other areas involved in reward processing, ghrelin can induce both general and directed motivation for rewards, including craving for alcohol and other alcohol-seeking behaviors. Stress-induced increases in cortisol seem to increase ghrelin in the periphery, suggesting a pathway by which ghrelin influences how stressful life events trigger motivation for rewards. However, in some states, ghrelin may be protective against the anxiogenic effects of stressors. This critical review brings together a dynamic and growing literature, that is, at times inconsistent, on the relationships between ghrelin, central reward-motivation pathways, and central and peripheral stress responses, with a special focus on its emerging role in the context of alcohol use disorder.

Keywords: Alcohol Craving; Ghrelin; Motivation; Reward Processing; Stress.

Figure 1. Central and peripheral actions of ghrelin: Simplified schematic of the complex interacting peripheral and central actions of ghrelin and cortisol

Ghrelin is synthesized primarily by endocrine cells in the stomach where it is acylated by the ghrelin O-acyl transferase (GOAT) enzyme. Acyl-ghrelin is released into the peripheral blood and crosses the blood-brain-barrier to reach the growth-hormone secretagogue receptor (GHS-R) on the hypothalamus (Hyp) and centrally-projecting Edinger-Westphal (EW) nucleus. In the hypothalamic arcuate nucleus (AN), acyl-ghrelin from periphery, and possibly from ghrelin-producing neurons, induces the release of neuropeptide Y (NPY), an orexigenic neuropeptide, stimulating appetite and ingestion. Acyl-ghrelin also acts at the hypothalamic paraventricular nucleus (PVN), where it stimulates NPY release. NPY release in turn inhibits GABA release, thereby stimulating corticotropin releasing factor (CRF) release, leading to adrenocorticotropic hormone (ACTH) release from the anterior pituitary (AP) to the adrenal cortex (AC). This cascade through the hypothalamic-pituitary-adrenal (HPA) axis causes the release of cortisol, which is also triggered by stress. Increased cortisol in the periphery causes increased peripheral acyl-ghrelin, suggesting a mechanism whereby states of stress can increase ghrelin and cortisol, which intrinsically covary and increase in parallel. Acyl-ghrelin also activates ventral tegmental area (VTA) neurons by binding to GHS-R’s and causing the release of dopamine in the nucleus accumbens (NAc). This mesolimbic dopamine projections result in increased reward processing, motivated behaviors and cravings, including craving for alcohol. Peripheral ghrelin levels are reduced during acute alcohol intake in healthy volunteers and in actively drinking individuals with chronic alcohol use disorder (AUD). On the other hand, peripheral ghrelin levels are increased during abstinence in individuals with chronic AUD. Peripherally, GHS-R are also synthesized and expressed in cells of the nodose ganglion (ND) with stomach-projected vagal afferent fibers. Peripheral acyl-ghrelin also acts via its GHS-R at the vagus nerve. The nucleus tractus solitarius (NTS), located at the medulla oblongata, receives information via the vagal afferent pathway and signals to the AN to induce appetite and ingestion.