Alterações comportamentais mediadas pelo etanol em peixe-zebra: influência do estresse oxidativo, disfunção mitocondrial e modulação serotoninérgica

Abstract

Ethanol consumption is a serious public health problem due to the negative impacts that affect individuals and society. Because the mechanism of action of ethanol in the central nervous system is complex and not fully understood, the drugs available to treat alcohol use-related disorders are not effective. Thus, the validation of new experimental models for translational studies of alcohol-induced disorders is important. The zebrafish (Danio rerio) has been used successfully to investigate the mechanisms related to ethanol abuse and addiction. However, several biochemical and behavioral features of ethanol exposure protocols in zebrafish still need to be explored. In the present study, we used acute and chronic ethanol exposure protocols in zebrafish to investigate biochemical aspects related to oxidative stress, bioenergetics, and the potential involvement of the serotonergic system in the neurobehavioral responses induced by alcohol. In a first study, we found that chronic exposure to ethanol (1.0% v/v) for 20 minutes for 8 days induced an anxiogenic effect, increasing social behavior and promoting oxidative stress. When assessing the effects of ethanol on mitochondrial respiration in the second study, we observed that acute exposure to ethanol (1.0% v/v for 1 hour) stimulated the oxidative phosphorylation process and increased the functionality of mitochondria in zebrafish brain, while the chronic exposure, similar to the protocol of the first study, impaired the transfer of electrons between I and II complexes of the mitochondrial respiratory chain. In the third study, we evaluated the involvement of the serotonergic system in acute responses to ethanol. Ethanol-induced aggressive behavior (0.25% v/v for 1 hour) is modulated by the serotonergic pathway with the main action of the 5-HT2A receptor, while the anxiolytic-like responses observed after exposure to a moderate concentration of ethanol (0.5% v/v for 1 hour) are modulated mainly by the 5-HT1B receptor. Depressive responses induced by ethanol (1.0% v/v for 1 hour) were not modulated by serotonergic drugs. In summary, similarly to what occurs in humans, we found that the responses mediated by ethanol in different experimental protocols involve changes in social behavior, oxidative stress, mitochondrial dysfunction, and serotonergic modulation in zebrafish. Our findings help elucidate the central mechanisms of action of ethanol and associated behaviors, reinforcing the predictive, face, and construct value of ethanol exposure models in zebrafish. These new results will allow the expansion of translational studies using this model organism in scientific research aimed at elucidating the mechanisms underlying the alcohol abuse and addiction.