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Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies.

ABSTRACT: The ghrelin system has been garnering interest for its role in different neuropsychiatric disorders, including alcohol use disorder (AUD). Accordingly, targeting the ghrelin system is under investigation as a potential novel therapeutic approach. While alcohol provokes the immune system and inflammatory responses, ghrelin has potent immunomodulatory and anti-inflammatory properties. The present study aimed to shed light on the "crosstalk" between ghrelin and inflammation by examining the effects of exogenous ghrelin administration and ghrelin receptor blockade on peripheral inflammatory markers in the context of two human laboratory studies with alcohol administration. Non-treatment-seeking, heavy-drinking individuals with alcohol dependence, the majority of whom were African American males, were enrolled. In the first randomized, crossover, double-blind, placebo-controlled human laboratory study, participants underwent two experimental paradigms - an intravenous alcohol self-administration (IV-ASA) and an intravenous alcohol clamp (IV-AC) - each consisting of two counterbalanced sessions (ghrelin, placebo). A loading dose of intravenous ghrelin (3 mcg/kg) or placebo, followed by a continuous ghrelin (16.9 ng/kg/min) or placebo infusion was administered. In the second dose-escalating, single-blind, placebo-controlled human laboratory phase 1b study, participants were dosed with an oral ghrelin receptor blocker (PF-5190457) and underwent an oral alcohol challenge. Repeated blood samples were collected, and plasma concentrations of the following inflammatory markers were measured: C-reactive protein (CRP), interleukin (IL)-6, IL-10, IL-18, and tumor necrosis factor alpha (TNF-α). During the IV-ASA experiment, significant drug × time interaction effects were observed for IL-6 (F_3,36 = 3.345, p = 0.030) and IL-10 (F_3,53.2 = 4.638, p = 0.006), indicating that ghrelin, compared to placebo, significantly reduced blood concentrations of the proinflammatory cytokine IL-6, while increasing blood concentrations of the anti-inflammatory cytokine IL-10. No significant drug × time interaction effects were observed during the IV-AC experiment, possibly because of its much shorter duration and/or smaller sample. Treatment with PF-5190457, compared to placebo, had no significant effect on the inflammatory markers investigated. In conclusion, a supraphysiologic pharmacological challenge with exogenous ghrelin in heavy-drinking individuals produced anti-inflammatory effects in the context of intravenous alcohol administration. On the contrary, ghrelin receptor blockade did not lead to any change in the inflammatory markers included in this study. Mechanistic studies are required to better understand the interaction between ghrelin, alcohol, and inflammatory processes.

SUBMITTER: Farokhnia M

PROVIDER: S-EPMC8715722 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGhrelin may influence several alcohol-related behaviors in animals and humans by modulating central and/or peripheral biological pathways. The aim of this exploratory analysis was to investigate associations between ghrelin administration and the human circulating metabolome during alcohol exposure in nontreatment seeking, heavy drinking individuals with alcohol use disorder (AUD).MethodsWe used serum samples from a randomized, crossover, double-blind, placebo-controlled human laboratory study with intravenous (IV) ghrelin or placebo infusion in two experiments. During each session, participants received a loading dose (3 µg/kg) followed by continuous infusion (16.9 ng/kg/min) of acyl ghrelin or placebo. The first experiment included an IV alcohol self-administration (IV-ASA) session and the second experiment included an IV alcohol clamp (IV-AC) session, both with the counterbalanced infusion of ghrelin or placebo. Serum metabolite profiles were analyzed from repeated blood samples collected during each session.ResultsIn both experiments, ghrelin infusion was associated with an altered serum metabolite profile, including significantly increased levels of cortisol (IV-ASA q-value = 0.0003 and IV-AC q < 0.0001), corticosterone (IV-ASA q = 0.0202 and IV-AC q < 0.0001), and glycochenodeoxycholic acid (IV-ASA q = 0.0375 and IV-AC q = 0.0013). In the IV-ASA experiment, ghrelin infusion increased levels of cortisone (q = 0.0352) and fatty acids 18:1 (q = 0.0406) and 18:3 (q = 0.0320). Moreover, in the IV-AC experiment, ghrelin infusion significantly increased levels of glycocholic acid (q < 0.0001) and phenylalanine (q = 0.0458).ConclusionIV ghrelin infusion, combined with IV alcohol administration, was associated with increases in the circulating metabolite levels of corticosteroids and glycine-conjugated bile acids, among other changes. Further research is needed to understand the role that metabolomic changes play in the complex interaction between ghrelin and alcohol.

Project description:Motivational models of alcohol use suggest that individual differences in sensitivity to the acute subjective effects of alcohol play an important role in motivational pathways to alcohol use. However, few studies have examined the link between drinking motives and subjective responses to alcohol. This study investigated the associations of coping and enhancement drinking motives with subjective stimulant and sedative effects during a laboratory alcohol administration session. We also examined whether stimulation and sedation following alcohol administration mediated the relationships between drinking motives and postalcohol ratings of alcohol wanting and liking.Heavy episodic drinkers (n = 147, ages 19 to 25) at 2 sites participated in an intravenous alcohol administration session in which blood alcohol concentration was raised to a target of 80 mg% over 20 minutes. Participants completed measures of stimulation and sedation at baseline and 20 minutes and also rated alcohol liking and wanting at 20 minutes. Drinking motives and alcohol use were assessed during a previous laboratory visit.A path analysis controlling for baseline stimulation and sedation showed that enhancement motives were positively associated with postalcohol stimulation and negatively associated with postalcohol sedation. In contrast, coping motives were positively associated with postalcohol sedation. In turn, postalcohol stimulation, but not sedation, was associated with alcohol wanting and liking. Further, indirect pathways from enhancement motives to postalcohol wanting and liking mediated through postalcohol stimulation were statistically significant. Coping motives, on the other hand, were directly associated with increased postalcohol wanting and liking.The results demonstrate that drinking motives are linked with individual differences in sensitivity to the effects of alcohol, which may serve as a mechanism underlying alcohol reinforcement and the motivation to consume more alcohol during a drinking episode.

Project description:Increasing evidence supports a role for appetite-regulating pathways like ghrelin, insulin, and leptin in alcoholism. We previously reported that intravenous (i.v.) exogenous ghrelin increases alcohol craving. We also reported i.v. ghrelin reduces endogenous serum leptin, whose levels, in turn, negatively correlated with alcohol craving. Exogenous ghrelin administration decreases insulin secretion both in vitro and in vivo experiments. This study tested the hypothesis that i.v. ghrelin may also decrease endogenous serum insulin levels in alcoholic individuals. Additionally, we explored possible correlations between serum insulin and alcohol craving, since a correlation between insulin and alcohol craving was previously reported. This was a double-blind, placebo-controlled human laboratory study ( n =43). Non-treatment-seeking, alcohol-dependent, heavy drinkers were randomized to receive i.v. ghrelin or placebo, followed by an alcohol cue-reactivity procedure. There was a main effect for i.v. ghrelin, compared to placebo in reducing serum insulin ( P <.05). There was also a time effect ( P <.001) but not ghrelin x time interaction ( P >.05). We did not find a correlation between the reduction of serum insulin and alcohol craving ( P >.05). The change in serum insulin was consistent with a parallel reduction in serum connective-peptide in the ghrelin group compared with placebo, although this difference did not reach statistical significance ( P =.076). No similar effects were found for other glucose-regulating hormones analyzed i.e. glucagon, glucagon-like peptide-1, and gastric inhibitory peptide ( P s>.05). These findings indicate i.v. ghrelin administration has an effect on reducing serum insulin in alcohol-dependent individuals; however, the reduction of insulin did not correlate with changes in alcohol cue-elicited craving. We speculate that, unlike for leptin, the interactions between ghrelin and insulin relationship are limited at the peripheral level. However, mechanistic studies are needed to investigate this hypothesis.

Project description:BackgroundMost physiological studies interested in alcohol-dependence examined ethanol as a pharmacological agent rather than a nutrient. We conducted two studies, which assessed the metabolic and endocrine factors involved in the regulation of alcohol and nutrient intake in alcohol-dependent (AD) subjects. We also examined the potential role of a disruption in energy balance in alcohol-dependence.Methods and resultsIn Study-1, quantitative dietetic interviews of eating and drinking habits were conducted with 97 AD subjects. The population was split around a median alcohol intake value of 12.5 kcal/kg/day. The results showed that the "low alcohol" drinking AD subjects had high Body Mass Index (BMI) and Fat Mass (FM) and alcohol intake was compensated for by a decrease in non-alcoholic intakes. "High alcohol" drinking AD subjects, on the other hand, had low BMI and FM and the total caloric intakes were largely above norms. In Study-2, 24 AD inpatients were submitted to dietetic interviews, calorimetry and blood samplings for the measurement of biomarkers of the regulation of metabolism and satiety, on day 2, 5 and 16 of abstinence. These patients were compared with 20 controls matched for age and gender. We observed in AD patients an increase in cortisol, leptin and PYY plasma levels and a decrease in ghrelin, which might explain the observed decrease in non-alcoholic intakes. However, alcoholic and non-alcoholic intakes correlated positively with basal metabolism and negatively with leptin and leptin/BMI.ConclusionFor individuals consuming below 12.5 kcal/kg/day of alcohol, alcohol intake is compensated for by a decrease in non-alcoholic nutrient intakes, probably due to changes in metabolic and satiety factors. For individuals consuming above 12.5 kcal/kg/day of alcohol, alcohol accelerates metabolism and decreases fat mass and leptin levels, and the total caloric intake largely exceeds norms. A dual model for regulation of energy intake in AD subjects is proposed.

Project description:There is sparse evidence regarding the effect of alcohol-advertising exposure on alcohol consumption among heavy drinkers. This study aimed to assess the immediate effects of alcohol-promoting and alcohol-warning video advertising on objective alcohol consumption in heavy-drinking young adults, and to examine underlying processes.Between-participants randomized controlled trial with three conditions.Two hundred and four young adults (aged 18-25) who self-reported as heavy drinkers were randomized to view one of three sets of 10 video advertisements that included either (1) alcohol-promoting, (2) alcohol-warning, or (3) non-alcohol advertisements. The primary outcome was the proportion of alcoholic beverages consumed in a sham taste test. Affective responses to advertisements, implicit alcohol approach bias, and alcohol attentional bias were assessed as secondary outcomes and possible mediators. Typical alcohol consumption, Internet use, and television use were measured as covariates.There was no main effect of condition on alcohol consumption. Participants exposed to alcohol-promoting advertisements showed increased positive affect and an increased approach/reduced avoidance bias towards alcohol relative to those exposed to non-alcohol advertisements. There was an indirect effect of exposure to alcohol-warning advertisements on reduced alcohol consumption via negative affect experienced in response to these advertisements.Restricting alcohol-promoting advertising could remove a potential influence on positive alcohol-related emotions and cognitions among heavy-drinking young adults. Producing alcohol-warning advertising that generates negative emotion may be an effective strategy to reduce alcohol consumption. Statement of contribution What is already known on this subject? Exposure to alcohol advertising has immediate and distal effects on alcohol consumption. There is some evidence that effects may be larger in heavy drinkers. Alcohol-warning advertising has been found to have mixed effects on alcohol-related cognitions. What does this study add? Among heavy-drinking young adults: Alcohol advertising does not appear to have an immediate impact on alcohol consumption. Alcohol advertising generates positive affect and increases alcohol approach bias. Alcohol-warning advertising that generates displeasure reduces alcohol consumption.

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Effects of exogenous ghrelin administration and ghrelin receptor blockade, in combination with alcohol, on peripheral inflammatory markers in heavy-drinking individuals: Results from two human laboratory studies.

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