Inhibition of Lrrk2 reduces ethanol preference in a model of acute exposure in zebrafish

Abstract

Due to its multifactorial and yet to be fully understood origin, ethanol addiction is a field that still requires studies for the elucidation of novel genes and pathways that potentially influence the establishment and maintenance of addiction-like phenotypes. In this context, the present study aimed to evaluate the role of the LRRK2 pathway in the modulation of ethanol preference behavior in Zebrafish (Danio rerio). Using the behavioral Conditioned Place Preference (CPP) paradigm, we accessed the preference of animals for ethanol. Next, we evaluated the transcriptional regulation of the gene lrrk2 and the receptors drd1, drd2, grin1a, gria2a, and gabbr1b in the zebrafish brain. Additionally, we used a selective inhibitor of Lrrk2 (GNE-0877) to assess the role of this gene in the preference behavior. Our results revealed four distinct ethanol preference phenotypes (Light, Heavy, Negative Reinforcement, and Inflexible), each showing different transcriptional regulation patterns of the drd1, drd2, grin1a, gria2a, and gabbr1b receptors. We showed that the lrrk2 gene was hyperregulated only in the brains of the animals with the Inflexible phenotype. Most importantly, we showed, for the first time in the context of preference for ethanol, that treatment with the GNE-0877 inhibitor modulates the transcription of the target receptor genes and reduces the preference for ethanol in the animals of the Inflexible group. This result corroborates the hypothesis that the LRRK2 pathway is involved in the inflexible preference for ethanol behavior. Lastly, we identified a possible pharmacological target for the treatment of abusive preference behavior for ethanol.