Ghrelin: From a Gut Hormone to a Potential Therapeutic Target for Alcohol Addiction

Abstract

Alcohol use disorder (AUD) is a chronic relapsing disease with significant medical, psychosocial, and economic burden. Pharmacological treatments for AUD are, however, limited in number and efficacy. Beyond classic neurotransmitter systems, there has been a growing interest in understanding the role of peripheral pathways (e.g., gut‐brain communications) in AUD, with the ultimate goal of identifying novel therapeutic targets. Ghrelin is an orexigenic peptide synthesized by enteroendocrine cells primarily located in the gastric mucosa. Ghrelin is known as the ‘hunger hormone’, given its role in stimulating both homeostatic and hedonic food intake. Ghrelin has also been shown to modulate alcohol seeking and consummatory behaviors, possibly through interactions with reward and stress pathways. Here we investigated whether and how pharmacological manipulation of the ghrelin system may affect biobehavioral correlates of alcohol use in heavy‐drinking alcohol‐dependent individuals. First, in a randomized, double‐blind, placebo‐controlled, human laboratory study, intravenous (IV) ghrelin/placebo was administered and two experiments were conducted: progressive‐ratio IV alcohol self‐administration (IV‐ASA) and brain functional magnetic resonance imaging (fMRI). Results showed that IV ghrelin, compared to placebo, significantly increased the number of alcohol infusions self‐administered (p=0.04) and reduced the time to initiate alcohol self‐administration (p=0.03). In addition, ghrelin increased the alcohol‐related signal in the amygdala (p=0.01) and modulated the food‐related signal in the medial orbitofrontal cortex (p=0.01) and nucleus accumbens (p=0.08). In the second study, we examined the effects of a novel ghrelin receptor inverse agonist (PF‐5190457) co‐administered with alcohol in both rodents and humans. No pharmacological interactions between alcohol and PF‐5190457 were found. PF‐5190457 did not interact with the effects of alcohol on locomotor activity or loss‐of‐righting reflex. In humans, PF‐5190457 was well tolerated, did not cause any significant side effect, and did not alter alcohol pharmacokinetics or alcohol‐induced subjective effects. As a secondary outcome, a cue‐reactivity procedure was also conducted in a bar‐like laboratory setting. Results showed that PF‐5190457, compared to placebo, reduced cue‐elicited craving for alcohol (p=0.05), as well as attention to alcohol cues (p=0.02). In conclusion, the ghrelin system seems to regulate both behavioral and neurobiological correlates of alcohol consumption and may represent a potential target for developing novel medications to treat AUD.Support or Funding InformationThis work was supported by A) NIH intramural funding ZIA‐AA000218 jointly supported by NIAAA and NIDA, and B) NCATS grant UH2/UH3‐TR000963. Development of the Computerized Alcohol Infusion System software was supported by the NIAAA‐funded Indiana Alcohol Research Center (AA007611). Pfizer provided the PF‐5190457 drug under the NCATS grant UH2/UH3‐TR000963 grant.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.