The association of the appetitive peptide acetylated ghrelin with alcohol craving in early abstinent alcohol dependent individuals

Abstract

Recent preclinical and clinical studies suggested ghrelin to have an orexigenic role in regulating appetite and energy balance. Preclinical studies also provided support for an important role of ghrelin in the neurobiology of addiction-related reward pathways, affecting the self-administration of alcohol and drugs as well as conditioned place preference. In contrast, clinical data have until now failed to support an association between ghrelin and alcohol craving, possibly due to the fact that these studies have analyzed the pharmacologically inactive, preprohormone ghrelin instead of ghrelin in its active, acetylated form. Our study sample was a group of 61 alcohol-dependent male inpatients. We assessed their plasma concentrations of both active and total ghrelin, using blood samples taken twice during the study: once at the onset of withdrawal, 12-24h after admission, and then again after 14 days of controlled abstinence. During this time, we also assessed the patients' alcohol cravings (applying the obsessive compulsive drinking scale, or OCDS), symptoms of depression (Beck Depression Inventory; BDI) and anxiety (State Trait Anxiety Inventory; STAI). The severity of alcohol dependence was assessed using the alcohol dependence scale (ADS). We found a significant positive correlation between the plasma concentration of active ghrelin and alcohol craving in both blood samples. Plasma concentrations of active ghrelin increased significantly during early abstinence. In a linear regression model, the plasma concentration of active ghrelin on day one, the scores of the ADS, and the BDI explained 36% of the variance in OCDS sum score (p<0.0001). By day 14, these same factors accounted for 54% (p<0.0001). We did not detect any association between the plasma concentration of total ghrelin and patients' alcohol cravings. Our results suggest that biologically active, acetylated ghrelin is involved in reward-associated craving during alcohol withdrawal and early abstinence in alcohol-dependent patients. Antagonizing ghrelin at its central growth-hormone secretagogue receptors (GHS-R1A) in the ventral tegmental area (VTA) may prove to be a novel pharmacological target in a future treatment for craving and relapse in alcoholics.