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    • According to the aforementioned preclinical and clinical dat

    2022-05-18

    According to the aforementioned preclinical and clinical data, GHS-R1a blockade appears to be a potential pharmacological approach to treat AUD. Given that GHS-R1a has high constitutive (ligand-independent) activity, inverse agonism of the receptor may exert more potent and desirable effects than pure competitive antagonism [129]. PF-5190457, an investigational drug acting as a GHS-R1a inverse agonist [130], is the first GHS-R1a blocker that has progressed to the human phases of medication development. A first-in-human phase 1a trial [131] indicated the safety and tolerability of this gamma-Glu-Cys in healthy individuals. In a phase 1b trial [132], we recently showed that PF-5190457 is safe and tolerable when co-administered with oral alcohol. PF-5190457 did not pharmacologically interact with alcohol; no meaningful differences in pharmacokinetic parameters were found between this phase 1b study in heavy-drinking individuals and the phase 1a study in healthy individuals. As a secondary outcome, we also conducted a cue-reactivity session in a bar-like laboratory, which showed that cue-elicited craving for both alcohol and food were reduced under PF-5190457, compared to placebo, in heavy alcohol drinkers [132]. A fully powered phase 2 trial with PF-5190457 in AUD patients is currently underway (ClinicalTrials.gov, NCT01779024).
    Conclusions and future directions Preclinical and clinical investigations of ghrelin have revealed its significant role in biobehavioral correlates of AUD. From endogenous measurements to genetic and pharmacological suppression of ghrelin signaling, alcohol-related outcomes appear to be causally influenced by the ghrelin system. From a mechanistic standpoint, this link is probably mediated through ghrelin's interactions with neurobiological pathways such as dopaminergic, GABAergic, serotonergic, and endocannabinoid systems [34,[133], [134], [135], [136], [137]]. More studies are indeed required to fully understand the underlying mechanism(s) through which ghrelin affects alcohol seeking and consumption behaviors. Of note, there is a considerable overlap between physiological processes (e.g. endocrine pathways) that regulate food craving/intake and drug addiction [7,138,139]. This notion is particularly relevant for alcohol, because alcohol not only is a CNS-acting drug but also has palatable properties and is a direct source of calorie. Taken together, the studies summarized in this review support the concept that manipulating the ghrelin system may represent a novel and potentially effective approach for AUD treatment. Pharmacological blockade of the ghrelin receptor has produced promising results in rodents, and this approach is currently under investigation in humans. Future studies should also work on developing and testing GHS-R1a negative allosteric modulators (NAMs), as these compounds may have more favorable pharmacological properties, compared to orthosteric ligands [[140], [141], [142]]. In addition to GHS-R1a, other components of the ghrelin system (e.g., GOAT, LEAP2) may also be investigated as druggable targets to develop novel medications for AUD. GOAT, an enzyme produced by endocrine cells of the stomach, is known as “master switch for the ghrelin system”, given that its action is required for acylation of des-acyl-ghrelin and, therefore, production of acyl-ghrelin [143]. While previous studies suggest that acyl-ghrelin can cross the blood-brain barrier [144,145], and may even be produced locally in the brain [146], there is strong evidence indicating that acyl-ghrelin's actions in the periphery (e.g., vagus nerve stimulation) are key for ghrelin system functions [147,148]. Of note, ghrelin receptors are expressed on the cell body of vagal afferent fibers, and ghrelin-induced food intake is abolished after vagotomy in rodents and humans [[149], [150], [151], [152]]. Accordingly, blocking ghrelin's acylation, via GOAT inhibition, may represent an effective pharmacological approach to suppress the activity of the ghrelin system [153,154]. Future studies could investigate whether GOAT inhibition may have beneficial effects on alcohol-related outcomes. Other pharmacological manipulations of the ghrelin system may also be examined in this regard, including (but not limited to) administration of des-acyl-ghrelin analogues, neutralization of acyl-ghrelin via vaccines, and administration or activation of LEAP2.