Efeitos da administração aguda e crônica de topiramato sobre as respostas comportamentais de ratos naive e abstinentes ao etanol

Abstract

Topiramate is an antiepileptic agent that has shown promise in treating migraine, obesity control and several psychiatric disorders, including bipolar disorder. Clinical studies report the use of topiramate for relief of behavioral impulsivity associated with abuse, cracking and psychological symptoms resulting from ethanol withdrawal. Considering its pharmacokinetic and pharmacodynamic properties and its high tolerability compared to the available clinical anxiolytics and antidepressants, it is interesting to investigate the anxiolytic and antidepressant potential of this drug in naive and ethanol abstinent rats.The present study investigated the effects of acute and chronic treatment with topiramate in behaviors related to anxiety, depression, and ethanol withdrawal after forced chronic consumption. Adult male Wistar rats were treated with topiramate (10 and 40 mg/kg/ml) or saline by gavage 60 minutes prior to the elevated plus maze tests (EPM), open field (OF) and forced swimming test (FST). It was observed that acute and chronic administration of topiramate (40 mg/kg/ml) promoted anxiolytic actions in naive animals and antidepressant effects after acute administration without impairment of locomotor activity. In another experimental series, rats were submetted to increasing concentrations of ethanol (2-6 %) for 21 days as the only source of liquid diet while the control group received water ad libitum. After chronic exposure, the ethanol was replaced by water, and the animals were evaluated in the EPM, OF, rota-rod, object recognition and FST. The rats chronically exposed to ethanol exhibited anxiogenic-like behavior 72 h after withdrawal. Furthermore, memory deficits and depressive-like behavior without alteration in locomotor activity and coordination were observed in protracted abstinent rats. In a third moment of this study, we evaluated the effect of acute and chronic administration of topiramate (40 mg/kg/ml) in the EPM, OF and FST in naïve and in early and protracted abstinent rats. Acute and chronic administration of topiramate (40 mg/kg/ml) induced anxiolytic-like effects in early and protracted abstinent rats, without affecting locomotion. By contrast, the chronic administration of topiramate did not counteract the depressive-related behavior of ethanol abstinent rats. Indeed, the acute administration of topiramate induces antidepressant-like effects in naive rats, but it dissipates after chronic treatment. In conclusion, topiramate showed anxiolytic effects after acute and chronic treatment in naive and abstinent rats. Additionally, acute topiramate induced antidepressive-like behavior in naïve rats, but this effect dissipates after chronic administration. The animal model herein proposed to study the ethanol abstinence induced anxiogenic- and depressive-like behaviors, similar to that found in humans through withdrawal. In this animal model, topiramate did not reverse the depressant-like effects of ethanol withdrawal. Finally, topiramate seems to be an interesting therapeutic approach for the treatment of anxiety, including that caused by ethanol abstinence.