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  • br Materials and methods br Conflicts of interest Some


    Materials and methods
    Conflicts of interest Some of the peptidomimetic compounds in this work are the subject of the patent application “Peptidomimetics for Imaging the Ghrelin Receptor”, WO/2016/191865 A1, December 8th, 2016.
    Acknowledgements Special thanks go to Rebecca McGirr (Lawson Health Research Institute) for the preparation of HEK293/ghrelin receptor cells for use in the receptor-ligand binding assays. We would also like to thank Prostate Cancer Canada and the Canadian Institutes of Health Research for funding this study.
    Background Alcohol use disorder (AUD) is a chronic relapsing disease characterized by allostatic changes in the brain's reward, stress, and executive function systems. AUD has a complex etiology and pathophysiology, as multiple genetic and environmental factors contribute to the development and progression of this disorder [1,2]. Despite the considerable medical, psychosocial, and economic burden associated with excessive alcohol use, treatment options for AUD, including pharmacotherapies, are limited in number and efficacy [3]. To date, most of the research in this regard has been focused on central mechanisms involved in AUD. Recently, there has been a growing interest in understanding the role of peripheral pathways (e.g., endocrine system, immune factors, gut microbiome) and their communication with the brain, with the ultimate goal of identifying novel therapeutic targets for addictive behaviors [[4], [5], [6], [7], [8]]. Notably, different components of the gut-brain axis have been shown to regulate normal behavioral functions, as well as pathophysiological processes that underlie neuropsychiatric disorders such as AUD [[9], [10], [11]]. One hormone that links the gastrointestinal and central nervous systems (CNS), and has begun to be investigated in relation to addictive behaviors, is ghrelin. Ghrelin is a 28-amino Nevirapine peptide synthesized by enteroendocrine cells primarily located in the gastric mucosa [12,13]. Preproghrelin is a precursor polypeptide (117 amino acids) encoded by the GHRL gene on chromosome 3; following post-translational cleavage, the ghrelin peptide is produced [14]. A fraction of this peptide, named des-acyl-ghrelin, is then modified by the ghrelin-O-acyltransferase (GOAT) enzyme to acyl-ghrelin [15]. Acyl-ghrelin is known as “active” ghrelin as it binds to and activates the ghrelin main receptor, named growth hormone secretagogue receptor 1a (GHS-R1a) [16]. While less is known about the physiological role of des-acyl ghrelin, some studies suggest that this peptide in not completely “inactive” [17,18]. GHS-R1a is a G protein-coupled receptor (GPCR) encoded by the GHSR gene on chromosome 3, and is widely expressed in both peripheral (e.g., gut, pancreas, thyroid, adipose tissue) and central (e.g., hypothalamus, ventral tegmental area, amygdala, hippocampus, Edinger-Westphal nucleus) tissues [[19], [20], [21]]. Notably, GHS-R1a has high constitutive (ligand-independent) activity [22] and forms heterodimers with other GPCRs, including GHS-R1b (i.e., another variant of the ghrelin receptor with less known functions), dopamine D1 and D2 receptors, serotonin 2C receptor, melanocortin 3 receptor, and somatostatin receptor 5 [[23], [24], [25]]. While ghrelin, GOAT, and GHS-R1a represent the mainly known components of the “ghrelin system”, a peptide primarily synthesized in the small intestines and the liver, named liver-expressed antimicrobial peptide 2 (LEAP2), has been recently identified as an endogenous antagonist of the GHS-R1a [[26], [27], [28]] (Fig. 1). Ghrelin is known as the “hunger hormone”, given its role in stimulating both homeostatic and hedonic food intake and regulating energy balance [[29], [30], [31], [32], [33]]. In addition to these key functions, ghrelin has been shown to influence neurobiological pathways underlying addictive behaviors. Specifically, ghrelin interacts with the mesolimbic dopaminergic system and plays an important regulatory role in reward processing [[34], [35], [36], [37], [38], [39]]. There is also a close link between ghrelin and stress-related mechanisms, indicating a role for ghrelin in processing negative emotional states [[40], [41], [42], [43]]. Moreover, ghrelin has been shown to be involved in neuroprotection, cognition, and executive functioning [[44], [45], [46], [47], [48], [49]]. Both preclinical and clinical studies suggest that alcohol consumption may have acute and chronic effects on the ghrelin system. In two independent rodent studies [50,51], alcohol intake altered peripheral concentrations of ghrelin in the blood, as well as gene expression of the ghrelin receptor in several brain regions, including nucleus accumbens (NAc), ventral tegmental area (VTA), amygdala, prefrontal cortex (PFC), and hippocampus. The magnitude and direction of these effects seemed to be dependent on alcohol preference, length of exposure, and amount of consumption, among other possible factors. Human laboratory studies have consistently shown that peripheral ghrelin levels are suppressed by both oral and intravenous acute alcohol administration [[52], [53], [54], [55], [56], [57]]. Most studies in alcohol-dependent individuals report that peripheral ghrelin levels are reduced during alcohol drinking and are increased during alcohol abstinence [[58], [59], [60], [61], [62], [63], [64]]. Finally, a recently published report from a large population-based study found a positive correlation between self-reported quantity of alcohol consumption and serum ghrelin concentrations [65].