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    • The effects of GHS R a blockade on

    2021-10-26

    The effects of GHS-R1a blockade on alcohol-related outcomes have been examined in numerous preclinical experiments, utilizing various GHS-R1a antagonists (JMV 2959, [D-Lys3]-GHRP-6, BIM 28163) and rodent species (prairie vole, mouse, rat). In spite of methodological differences, the results consistently show that GHS-R1a antagonism suppresses alcohol consumption and other related outcomes, including alcohol-induced accumbal dopamine release, hyperlocomotion, and conditioned place preference, the latter being a proxy of alcohol reward [84,86,[109], [110], [111], [112], [113], [114], [115], [116], [117]]. Notably, GHS-R1a antagonists were administred peripherally in most of the aforementioned studies, except for two experiments where intracerebroventricular [86] and intra-NAc [117] administration was employed. It has been proposed that off-target activity [118,119] and/or biased signaling [120,121] may be responsible for some of the pharmacological effects executed by GHS-R1a antagonists. Relevant to this notion, Bahi et al. [84] showed that the suppressant effects of a GHS-R1a antagonist (JMV 2959) on alcohol-induced hyperlocomotion and alcohol consumption/preference were abolished in GHRL knockout mice, suggesting that, at least for JMV 2959, the effects on alcohol-related outcomes are mediated through GHS-R1a blockade and not any other nonspecific pathway. It has also been speculated that inactivation of GHS-R1a may cause malaise, which may be partially responsible for the attenuating effects of GHS-R1a antagonism on reinforcing behaviors. A recent study [122], however, ruled out this LIMKi 3 by showing that the effects of JMV 2959 are unlikely to be mediated through inducing malaise. Preclinical data collectively suggest that the ghrelin system plays an important role in biobehavioral regulation of alcohol consumption and can be studied as a viable therapeutic target – building the groundwork for clinical studies to further probe this notion by translating the findings into human research. While observational studies in humans point to a strong correlation between endogenous ghrelin levels and alcohol-related outcomes, well-controlled interventional studies are required to examine a possible causal relationship in this regard. In a randomized, between-subject, double-blind, placebo-controlled, human laboratory study [123], we assessed the effect of exogenous ghrelin on alcohol craving in heavy-drinking alcohol-dependent individuals. Following a 10-min intravenous infusion of ghrelin (1 or 3 μg/kg) or placebo, participants underwent a cue-reactivity procedure in a bar-like laboratory. Results showed that intravenous administration of ghrelin (3 μg/kg), compared to placebo, significantly increased cue-induced craving for alcohol, with no significant effect on craving for juice. Post-infusion blood ghrelin concentrations were found to be positively correlated with the magnitude of increase in alcohol craving. This was the first study showing that the intensity of alcohol craving in humans may be modulated by a direct manipulation of the ghrelin system (i.e., intravenous ghrelin administration). Consistent results were found in a more recent study [124] which employed an indirect manipulation of endogenous ghrelin levels via forced water intake. A group of alcohol-dependent males were first exposed to alcohol cues to induce craving. Then, they were either asked to drink 1000 ml of still mineral water within 10 min (intervention group) or were not allowed to drink anything (control group). Forced water intake resulted in significant reduction of blood ghrelin levels (an effect possibly mediated by stomach distension), and the magnitude of this reduction was negatively correlated with the intensity of alcohol craving in the intervention group. In addition to craving, it is crucial to understand whether and how pharmacological manipulation of the ghrelin system may influence alcohol intake in humans. This is a key question, as establishing a causal role for ghrelin in alcohol consumption would further validate the therapeutic potential of this pathway for AUD. Accordingly, our group recently completed a randomized, crossover, double-blind, placebo-controlled human laboratory study in heavy-drinking alcohol-dependent individuals, testing the effects of exogenous ghrelin on alcohol self-administration and brain functional activity [125]. The study consisted of two experiments: intravenous alcohol self-administration (IV-ASA) and brain fMRI; each experiment included two visits during which intravenous ghrelin (a 10-min loading dose of 3 μg/kg, followed by a continuous infusion of 16.9 ng/kg/min) or placebo was administered. Using a computerized alcohol infusion system [126], participants were given the opportunity to press a button, with a progressive ratio schedule, in order to receive intravenous infusions of alcohol during the 2-h IV-ASA experiment. Results showed that participants self-administered significantly higher number of alcohol infusions under ghrelin than placebo. They also started pressing the button sooner and received their first infusion earlier during the ghrelin session. Moreover, intravenous ghrelin administration intensified subjective responses to alcohol (e.g., ‘feel high’), and exposure-response analyses found significant interactions between drug condition (ghrelin/placebo) and breath alcohol concentration on subjective effects of alcohol (i.e., ‘stimulation’, ‘like the effects’, ‘feel high’, and ‘feel intoxicated’). For the brain fMRI experiment, an alcohol-food incentive delay (AFID) task was used [127]; participants worked to gain points for alcohol, food, or no reward, while their brain functional activity was estimated via blood oxygen level dependent (BOLD) signal during anticipation phase of the task. Results showed that intravenous ghrelin significantly increased the amygdala activity in response to alcohol reward anticipation. In addition, under ghrelin, food-related signal was decreased in the medial orbitofrontal cortex (mOFC) and increased in the NAc, suggesting that distinct brain regions are primarily engaged by ghrelin in anticipation for alcohol (amygdala) versus food (mOFC, NAc) reward. In a secondary analysis [128], we also found that intravenous ghrelin administration significantly reduced the severity of alcohol hangover symptoms, potentially through interactions with inflammatory, oxidative stress, and/or metabolic pathways. Collectively, both behavioral and neurobiological correlates of alcohol use were modulated by a ghrelin pharmacological challenge, providing further rationale for studying the ghrelin system as a treatment target for AUD.