Taken together previous data suggest that

Taken together, previous data suggest that ghrelin signaling is causally linked to alcohol use and may regulate alcohol seeking and consummatory behaviors [[66], [67], [68]]. As such, the ghrelin system may represent a therapeutic target for AUD. Here, we provide a narrative review of the existing literature on the relationship between the ghrelin system and alcohol-related outcomes. Specifically, we discuss whether and how endogenous levels, genetic manipulation/variation, and pharmacological manipulation of the ghrelin system have been found to be associated with alcohol-related outcomes. The main findings in support of this notion are also summarized in Table 1.
Endogenous ghrelin levels and alcohol-related outcomes Craving, or intense desire, is a prominent correlate of alcohol use, that has been shown to predict the likelihood of relapse in AUD patients [69,70]. Self-reported assessments, such as obsessive-compulsive drinking scale (OCDS) and Penn alcohol craving scale (PACS), are the primary tool by which craving is measured in research studies. Functional magnetic resonance imaging (fMRI) has been also used to measure Thalidomide activity in response to alcohol cues in laboratory settings. The neurobiology of alcohol craving is complex, with multiple central and peripheral pathways being involved [69,71]. Ghrelin signaling seems to play a role, as numerous observational studies [58,61,62,[72], [73], [74], [75], [76]] (but see: [63,77]) have found that endogenous ghrelin levels in the blood positively correlate with the intensity of self-reported craving. One of these studies also found that individuals who continued drinking alcohol, despite receiving treatment, had higher blood ghrelin concentrations at baseline, compared to those who remained abstinent [61]. Accordingly, the authors proposed that baseline ghrelin levels may predict the likelihood of relapse to alcohol drinking. A recent study with a relatively different design failed to confirm this notion with ghrelin per se, yet showed that lower levels of leptin (a protein with physiological functions opposite to ghrelin) predicted shorter time to relapse [76]. Mechanistic studies are required to further explore these observations and to elucidate possible pathways through which ghrelin signaling may play direct and/or indirect roles in regulating alcohol craving and relapse. Subjective response to alcohol is another important determinant that has been shown to influence the risk/resilience of developing AUD [78,79]. It appears that the ghrelin system is involved in regulating subjective response to alcohol – a biobehavioral pathway that may, in part, mediate ghrelin's impact on alcohol-related outcomes. As part of a larger study which examined the relationship between family history of alcohol dependence and subjective response to intravenous alcohol administration, Ralevski et al. [57] measured blood ghrelin levels before, during, and after alcohol infusion in twenty healthy social drinkers, and found that baseline ghrelin levels significantly predicted the intensity/duration of subjective response to alcohol. Specifically, higher blood concentration of acyl-ghrelin at baseline was a significant predictor of higher sedation, feeling ‘buzzed’, ‘drowsy’, and ‘tired’. In an additional secondary analysis of the same study, Ralevski et al. [80] looked at the relationship between blood ghrelin levels and data collected via the behavioral inhibition & activation scales (BIS/BAS) at baseline. They found that higher blood concentrations of acyl-ghrelin were associated with more sensitivity to reward and less self-control. These preliminary results suggest that characteristics such as reward sensitivity and impulsivity may contribute to the interplay between the ghrelin system and alcohol-related behaviors; however, more studies are required to confirm these findings. In two recent studies conducted by the same group, brain fMRI was used to examine the brain regions/circuits that may mediate ghrelin's influence on alcohol-related behaviors. The first study [75] tested the relationship between blood ghrelin levels, mesolimbic reactivity to alcohol visual cues, and subjective ratings of alcohol craving in recently detoxified patients with alcohol dependence. Acyl-ghrelin concentrations were positively correlated with the brain response to alcohol cues in ventral striatum, insula, cerebellum, anterior cingulate cortex, and parts of frontal, temporal and occipital cortices. Consistent with this whole brain analysis, there was a significant positive correlation between blood concentrations of acyl-ghrelin and alcohol cue-induced activation in ventral striatum. Mediation analysis also showed that the brain response in ventral striatum fully mediated the link between blood concentrations of acyl-ghrelin and subjective ratings of alcohol craving. The second study [76] employed a similar methodology and found that acyl-ghrelin concentrations were positively correlated with the brain response to alcohol cues in insula, middle cingulum, and parts of superior and middle frontal gyri. Corroborating these findings, a significant positive correlation was shown between blood concentrations of acyl-ghrelin and alcohol cue-induced activation in insula. Unlike their first study, the authors did not perform mediation analysis to examine whether insula activation mediates the link between acyl-ghrelin concentrations and alcohol craving. Notably, unlike acyl-ghrelin, total ghrelin (i.e., acyl-ghrelin + des-acyl-ghrelin) levels were not significantly associated with alcohol cue-induced brain response in either of the aforementioned studies [75,76].