The impact of appetite regulating peptides on substance use disorders

Abstract

Background

Preclinical and clinical data suggest modulating effects of the appetite regulating peptide ghrelin on food intake. Recent data suggest that in food intake the “endostatic” energy-homeostatic systems of the lateral hypothalamus (LH) and the motivational, mesolimbic reward system operate in dynamic interplay with each other. Ghrelin receptors have been detected in the ventral tegmentum of the midbrain (VTA), where they modulate the activity of dopaminergic neurons projecting to the NAc. Assuming that Ghrelin modulate mesolimbic reactivity, the question remains: is this only the case in response to food cues? Or is this the case in response to reward-associated cues in general (including those related to nicotine and alcohol)?

Methods

Study 1: a consecutive sample of 61 alcohol-dependent male inpatients was included. Blood was drawn at onset of withdrawal 12-24 hours after admission, and following 14 days of controlled abstinence in order to assess plasma concentrations of both active and total ghrelin. In parallel, we assessed alcohol craving applying the Obsessive Compulsive Drinking Scale (OCDS) as well as symptoms of depression (Beck Depression Inventory [BDI]) and anxiety (State Trait Anxiety Inventory [STAI]). The severity of alcohol dependence was assessed with the Alcohol Dependence Scale (ADS). Study 2: 54 non-treatment seeking smokers and 30 healthy controls with normal eating behavior, as measured by the Three Factor Eating Questionnaire (TFEQ) participated in this study. We measured plasma concentrations of both active and total ghrelin, using a blood sample taken two hours after a standardized meal during early nicotine abstinence in the smoking group. Additionally we quantified severity of addiction in the smoking group using the number of cigarettes smoked per day, cotinine plasma concentration and the Fagerström Test for Nicotine Dependence (FTND).

Results

Study1: 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 < 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. Study 2: plasma concentration of acetylated ghrelin but not total ghrelin was significantly higher in smokers than in non-smokers. Moreover, we found significant negative correlations between acetylated ghrelin and all measures of the severity of nicotine dependence.

Discussion

In conclusion, both studies supports the general idea that ghrelin's central effects go beyond the endostatic regulation of energy homeostasis, also involving pathways underlying reward expectation and craving. Physiologic factors modulating the reactivity of mesolimbic pathways represent an important research topic for developing pharmacologic treatments for disorders characterized by altered reward-related behaviors, such as substance use disorders and behavioral addictions.

Disclosure of interest

The authors have not supplied their declaration of competing interest.