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  • Using data from a large

    2022-08-13

    Using data from a large population-based cohort study in Finnish males and females, Suchankova et al. [97] looked at a subset of the aforementioned SNPs, namely one SNP on GHSR (rs2948694) and two SNPs on GHRL (rs4684677 and rs696217), in relation to alcohol use disorders identification test (AUDIT) scores. They found that the minor allele of rs2948694 SNP on GHSR predicted higher AUDIT scores. Neither of the GHRL SNPs were associated with AUDIT scores. In a subsequent study, Suchankova et al. [98] focused on one GHRL SNP (rs696217) and utilized data collected at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), which included individuals with (case) or without (control) a lifetime diagnosis of AUD. The case-control analysis showed a trend-level association between the studied SNP and AUD diagnosis. Moreover, within the case group, the minor allele of this SNP was associated with lower levels of alcohol drinking, as assessed via Timeline Followback. Finally, in a subset of moderate non-dependent alcohol drinkers, the minor allele of this SNP was associated with higher subjective response to alcohol during an intravenous alcohol administration procedure. Overall, these genetic association studies are not conclusive and need to be replicated on a larger scale and by independent research groups. If confirmed, the next step will be to examine whether and how these genetic variants are mechanistically linked to alcohol-related behaviors.
    Pharmacological manipulation of the ghrelin system and alcohol-related outcomes Several preclinical experiments, conducted by independent research groups and using diverse rodent models and methods, have investigated whether and how pharmacological manipulation of the ghrelin system may affect alcohol-related outcomes. These studies have employed peripheral (systemic) or central administration of either the ghrelin peptide or a ghrelin SKF 96365 hydrochloride sale antagonist to respectively activate or suppress the ghrelin system. In a series of experiments, Lyons et al. [99] sought to investigate whether increased alcohol drinking during the DID paradigm may stem from caloric need. Intraperitoneal administration of ghrelin in mice had no significant impact on alcohol intake in this study. A similar result was observed following other interventions, including food deprivation and intraperitoneal administration of leptin. As part of another study investigating the effects of gastric bypass surgery on alcohol consumption, Davis et al. [100] performed Roux-en-Y gastric bypass (RYGB) surgery in ethanol-preferring (P) rats, which were first made obese via high-fat diet. The RYGB surgery resulted in significant suppression of alcohol consumption (assessed 36 days after the surgery via a two-bottle free-choice paradigm), compared to the sham group. They also examined whether systemic administration of ghrelin or a GHS-R1a antagonist (JMV 2959), injected 30 min prior to alcohol exposure, altered the amount of alcohol consumption in these rats. Results showed that exogenous ghrelin administration restored the alcohol consummatory behavior in RYGB P rats by significantly increasing the amount of alcohol intake, but had no significant effect on alcohol intake in the sham group. In parallel, GHS-R1a antagonism significantly reduced the amount of alcohol intake in the sham but not in the RYGB group, suggesting that ghrelin signaling is required for elevated alcohol consumption in ethanol-preferring rats. Of note, a team led by the Hajnal lab found that RYGB in diet-induced obese Sprague Dawley rats increased alcohol drinking [[101], [102], [103]] – a finding later replicated by Davis et al. [104] in diet-induced obese Long–Evans rats and consistent with several clinical observations (for review, see: [105]). Hajnal et al. also found that systemic administration of a GHS-R1a antagonist (D-[Lys3]-GHRP-6) resulted in reduced alcohol drinking in RYGB rats but not in the sham group [103]. Both peripheral (intraperitoneal) and central (intra-VTA) administration of ghrelin increased alcohol intake in rats [106], but central administration of ghrelin into paraventricular nucleus (PVN), lateral hypothalamus (LH), or NAc did not have a significant effect on alcohol consumption [107]. In an effort to disentangle the role of peripheral versus central ghrelin signaling in alcohol-related behaviors, rodents were pre-treated with an anti-ghrelin l-oligonucleotide (Spiegelmer NOX-B11-2), which neutralizes acyl-ghrelin in the periphery and blocks its entrance into to brain. Systemic administration of Spiegelmer NOX-B11-2, compared to vehicle, had no significant effect on alcohol intake or alcohol-induced accumbal dopamine release, hyperlocomotion, or conditioned place preference, providing preliminary evidence that central, rather than peripheral, ghrelin signaling is involved in modulating alcohol-related behaviors [108]. However, fully factorial experiments (e.g., adding an experiment to block central, but not peripheral, ghrelin signaling) are required to better address this question. In a comprehensive set of experiments, Jerlhag et al. [86] showed that central administration of ghrelin into mice brain ventricles (intracerebroventricular), VTA, or laterodorsal tegmental nucleus (LDTg) significantly increased alcohol intake in a two-bottle free-choice paradigm. Interestingly, GHSR knockout mice did not show increased alcohol intake in response to central ghrelin administration (only intracerebroventricular, and not intra-VTA or intra-LDTg, was tested in knockout mice), suggesting that GHS-R1a is required for ghrelin's effects on alcohol consumption. In a follow-up study, Jerlhag et al. [82] replicated their finding that intracerebroventricular administration of ghrelin increases alcohol intake. However, unlike their previous observation in GHSR knockout mice, ghrelin-induced increase in alcohol consumption was not different between GHRL knockout and wild-type mice. These findings suggest that pharmacological manipulation of the ghrelin system, especially GHS-R1a, may be considered as an approach to regulate alcohol seeking and consummatory behaviors.