Efeitos do ácido lipóico em diferentes fases de desenvolvimento de camundongos em modelo de preferência ao etanol

Abstract

In Brazil, it is estimated that 11.7 million people are dependent on alcohol, and although it is a millenar complication of health, the available treatments have limited effectiveness. Lipoic acid, a powerful antioxidant, has shown to interfere on mechanisms related to drug abuse. Adolescence represents a period of high neuroadaptive vulnerability. The present study raises the hypothesis that lipoic acid may influence the preference to ethanol at different stages of development. Thus, this research investigated the action of lipoic acid during the developmental period since adolescence until young adulthood on the reinforcing effects of ethanol. Male Swiss mice were used for the three protocols (acute-adolescent, acute-adult; chronic) with different animals for each group. In acute-adolescent protocol, animals with 35 postnatal days (PND) were acutely treated with ethanol (EtOH) (2 g/kg, p.o.), lipoic acid (LA) (100 mg/kg, p.o.) or association (LA+EtOH) and subjected to behavioral tests open field, Y-maze and conditioned place preference (PCL). In the acute-adult protocol, animals with 72 PND were exposed to the same procedures. Chronic protocol was initiated with animals over 35 PND treated for 14 days with vehicle or LA. After this animals were treated for 21 days with EtOH or LA+EtOH. Behavioral tests were then started from 72 PND. After behavioral tests, the animals brain were used for neurochemical analysis involving dosage of BDNF, cytokines (TNF and IL-6), TBARS and GSH. Lipoic acid behaved in different ways according to the period of life in which was used. On adolescence LA was able to prevent EtOH-induced locomotor activity, but in adulthood it presented stimulant effect. Memory was impaired with acute (in adolescence) and chronic EtOH exposure, and LA had no preventive effect on memory impairment on adolescence but was able to prevent memory deficits induced by chronic EtOH. While in adolescence LA induced CPP when acutely administered prior to EtOH, on adulthood the same treatment was able to prevent the acquisition of EtOH-induced CPP. LA administration chronically with EtOH induced strong sensitization for ethanol preference. No preventive effect of LA during adolescence was observed in chronic EtOH-induced CPP. No significant alteration on BDNF concentration was observed with acute EtOH administration, but chronic exposure to this drug until young adulthood decreased it. BDNF was also reduced in groups treated with the association of LA and EtOH both acutely and chronically over adolescence. Cytokines IL-6 and TNFα behaved in a similar way for both acute and chronic treatment. Acute treatment with EtOH or LA did not change cytokine concentrations, but LA administration prior to EtOH induced a significant decrease of them. When chronically administered over adolescence EtOH curiously decreased cytokine concentrations, independently of the association with LA. The increase of GSH levels was observed when LA and LA+EtOH were acutely administered in adolescence (PFC and ST) and in all groups that received chronically EtOH with or without association to LA since adolescence over young adulthood (ST). A decrease in lipid peroxidation was shown on EtOH acute treatment, while chronic EtOH administration increased this parameter. LA was able to prevent this raise of EtOH-induced lipid peroxidation when co-administered with it since adolescence until young adulthood. Our data suggest that ethanol acts in different way depending of treatment time and developmental stage, having in some cases its effects prevented by LA. Lipoic acid effects strongly depends of the period in which is administered, and can interact in different way with reinforcing effects of ethanol. Furthermore, LA fail to reduce long-term degenerative effects induced by ethanol and shows reinforcing effects on behavioral and neurochemical rewarding properties elicited by ethanol-induced preference.