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  • Praziquantel receptor br Genetic manipulation variation of t

    2022-01-12


    Genetic manipulation/variation of the ghrelin system and alcohol-related outcomes Genetic manipulation of the ghrelin system (either the peptide or the receptor gene) via knockout rodent models has provided further insight into the role of this system in alcohol seeking and consummatory behaviors. Using a previously developed GHRL knockout mouse model [81], Jerlhag et al. [82] showed that alcohol-induced accumbal dopamine release and hyperlocomotion are suppressed in GHRL knockout mice, compared to wild-type animals. This study, however, did not find any difference across genotypes in spontaneous alcohol intake during a limited-access paradigm [83]. In another study using a different knockout model, Bahi et al. [84] found that, in addition to alcohol-induced hyperlocomotion and conditioned place preference, alcohol consumption and preference (but not total fluid intake) were also suppressed in GHRL knockout mice. It is important to note that, in comparison with the experiment conducted by Jerlhag et al. [82], a different alcohol drinking paradigm, i.e., two-bottle free-choice (for details on this paradigm, see e.g. [85]), was employed in this study [84]. Importantly, the observed effects appear to be specific to alcohol, and palatability does not seem to play a role, as no significant effect of Praziquantel receptor was observed when the same paradigm was conducted with a sweet (saccharin) or a bitter (quinine) drink, instead of alcohol. As part of a comprehensive set of experiments [86], a previously developed GHSR knockout mouse model [87] was used to investigate the role of GHS-R1a in alcohol reward. Compared to the wild-type, GHSR knockout mice showed significantly lower alcohol-induced accumbal dopamine release, hyperlocomotion, and conditioned place preference, but no significant effect of genotype on spontaneous alcohol intake (limited-access paradigm [83]) was found. Our group has recently developed and characterized a new GHSR knockout rat model using CRISPR/Cas9 technology, which provides an additional tool to study the ghrelin system in relation to biological and behavioral processes [88]. Utilizing this model, we examined drinking behaviors of GHSR knockout versus wild-type rats via three different paradigms that model varying degrees and patterns of alcohol consumption: operant binge-like self-administration [89], drinking in the dark (DID) [90], and intermittent alcohol access [91]. Significant genotype effects were found during more intense/short-term drinking paradigms. Specifically, GHSR knockout rats self-administered less alcohol than wild-type rats during the operant binge-like self-administration paradigm, which used a sweetened alcohol solution. Notably, this effect was specific for alcohol, as self-administration of the sweetened solution in absence of alcohol was not different between the two genotypes. For the DID paradigm, no significant difference between GHSR knockout and wild-type rats was observed in aggregate analyses. However, within the high-drinking sub-group (based on median split), GHSR knockout rats consumed significantly less alcohol than wild-type rats during initial stages of this paradigm. No significant genotype effect was found during the intermittent access paradigm [92]. Genetic association studies in humans have examined the relationship between the ghrelin peptide and receptor gene variants and alcohol-related outcomes. In their first study, Landgren et al. [93] looked at four single nucleotide polymorphisms (SNPs) on GHSR (rs495225, rs2232165, rs572169, and rs2948694) and six SNPs on GHRL (rs696217, rs3491141, rs4684677, rs35680, rs42451, and rs26802) among individuals with different drinking levels (i.e., alcohol abstainers, moderate drinkers, and heavy drinkers). They found that the genotype of one SNP on GHSR, but none on GHRL, was associated with levels of alcohol consumption. In a second study [94], the same team looked at the same SNPs in a sample of females with severe alcohol dependence, compared to a control sample of females with low drinking levels. No significant genotype differences were detected between the two groups, but a few significant associations with alcohol-related parameters were found within the case group (i.e., females with severe alcohol dependence). Specifically, one haplotype on GHSR was positively correlated with type 2 alcohol dependence, which is characterized by early age of onset, high heritability, and social/legal problems [95]. Genetic variation of GHRL was also found to be associated with (a) paternal alcohol dependence and (b) alcohol withdrawal symptoms. In their third study, Landgren et al. [96] investigated the relationship between personality traits and several SNPs on eight reward-related genes, including the aforementioned SNPs on GHSR and GHRL. No significant differences were found between cases (i.e., individuals with alcohol dependence) and controls (i.e., individuals with non-harmful alcohol consumption). However, GHSR and GHRL variants were, respectively, associated with self-directedness and self-transcendence traits.