Neuroendocrine Response to Exogenous Ghrelin Administration, Combined With Alcohol, in Heavy-Drinking Individuals: Findings From a Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study

Abstract

Background Accumulating evidence has established a role for the orexigenic hormone ghrelin in alcohol seeking behaviors. Accordingly, the ghrelin system may represent a potential pharmacotherapeutic target for alcohol use disorder (AUD). Ghrelin modulates several neuroendocrine pathways, such as appetitive, metabolic and stress-related hormones, which are particularly relevant in the context of alcohol use. The goal of the present study was to provide a comprehensive assessment of neuroendocrine response to exogenous ghrelin administration, combined with alcohol, in heavy-drinking individuals. Methods This was a randomized, crossover, double-blind, placebo-controlled human laboratory study, which included two experimental alcohol administration paradigms: intravenous alcohol self-administration (IV-ASA) and intravenous alcohol clamp (IV-AC). Each paradigm consisted of two counterbalanced sessions of IV ghrelin or placebo administration. Repeated blood samples were collected during each session, and peripheral concentrations of the following hormones were measured: leptin, glucagon-like peptide-1 (GLP-1), pancreatic polypeptide (PP), gastric inhibitory peptide (GIP), insulin, insulin-like growth factor-1 (IGF-1), cortisol, prolactin, and aldosterone. Results Despite some statistical differences, findings were consistent across the two alcohol administration paradigms: IV ghrelin, compared to placebo, increased blood concentrations of GLP-1, PP, cortisol, and prolactin, both acutely and during the whole session. Lower levels of leptin and higher levels of aldosterone were also found during the ghrelin versus placebo session. Conclusion These findings, gathered from a clinically relevant sample of heavy-drinking individuals with AUD, provide a deeper insight into the complex interplay between ghrelin and appetitive, metabolic, and stress-related neuroendocrine pathways in the context of alcohol use.

Effect of intravenous ghrelin administration, combined with alcohol, on circulating metabolome in heavy drinking individuals with alcohol use disorder

“…The observed effect of IV ghrelin infusion in increasing peripheral corticosteroids levels aligns with, and expands, previous literature showing that ghrelin administration increases cortisol levels in rodents (Asakawa et al, 2001) and in humans (Farokhnia et al, 2021;Haass-Koffler et al, 2019). The association between corticosteroids and ghrelin seems to be bidirectional, since acute stress increases ghrelin levels, whereas chronic stress blunts this response (Fahrngruber-Velasquez et al, 2021).…”

“…We have previously shown increased cortisol levels following ghrelin infusion using chemiluminescence immunoassays in blood samples from the same study, where we analyzed a small number of stress-and feeding-related peripheral hormones that were selected a priori (Farokhnia et al, 2021). In the present study, we employed a hypothesis-free exploratory approach via nontargeted LC-MS metabolomics.…”

Ghrelin octanoylation by ghrelin O -acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling

“…These pathways include glucose metabolism and energy homeostasis [ 10 – 15 ], organismal response to starvation [ 16 – 19 ], cardio-protection [ 20 , 21 ], protection against muscle atrophy [ 22 – 24 ] and bone metabolism [ 9 , 25 ]. Recent studies suggest ghrelin is involved in the mediation of behavioural and biochemical effects of drugs linked to addiction and addictive behaviour [ 26 – 31 ]. Ghrelin is also linked to signalling pathways linked to learning, memory, reward processing and stress response [ 32 – 38 ].…”

“…These pathways include glucose metabolism and energy homeostasis [10][11][12][13][14][15], organismal response to starvation [16][17][18][19], cardio-protection [20,21], protection against muscle atrophy [22][23][24] and bone metabolism [9,25]. Recent studies suggest ghrelin is involved in the mediation of behavioural and biochemical effects of drugs linked to addiction and addictive behaviour [26][27][28][29][30][31].…”

Current View on the Mechanisms of Alcohol-Mediated Toxicity

“…In addition to acute intoxications, which often require urgent care attention, especially in young people, the danger of alcohol consumption lies primarily in alcohol addiction, leading to chronic abuse and organ damage. Affected organs/systems include the liver [2], the cardiovascular system [3], the endocrine system [4], the metabolism of basic nutrients [5], the neural system [6,7], or the gastrointestinal tract [8]. Although the mentioned organs/systems perform different functions, the distribution and metabolization of ethanol in organs/systems are variable.…”