Influence of vigabatrin behaviour in rats upon diazepam withdrawal

ABSTRACT

Frequent administration of diazepam has been reported to induce physical dependence and tolerance in animals and humans. Using an elevated plus-maze model of anxiety, we investigated whether vigabtrin reduces some of withdrawal symptoms of diazepam. Vigabatrin is irreversible inhibitor of the enzyme GABA-transaminase, which induces several increases in brain GABA levels. Previously, treatment of rats with vigabatrin for 14 days was found to produce an anxiolytiiclike effect without a changes in the general locomotor activity. In this study, rats were chronically treated with either diazepam at a dose of 10mg/kg/day, i.p. or vigabatrin at a dose of 200mg/kg/day, i.p. alone or in combination at a dose of 10mg/kg/day diazepam+200mg/kg/day for ivgabatrin for 14 days to examine their effects. The general locomotor activity of the rats did not alter in both groups of tolerance and dependence in comparison with control rats. An increases of horizontal activity of diazepam-dependent rats after 48 hrs of the last injections was observed without a changes in the vertical activity. In the dependence group, the anxiolytic effect of chronic treatment with diazepema was found to persist 48 hrs after last injection. However, the combined treatment of diazepam wth vigabatrin completely abolished the anxiolytic effect of diazepam [10mg/kg]. In the tolerance groups, the effect of 1.5mg/kg diazepam in chronically diazepam-treated rats was significantly lower than that of the control and chronically diazepam and vigabtrin-treated rats, with no difference between control group and combined treatment group. Forty-eight hours after the last injection, the concentration of GABA in the frontal cortex was significantly higher in the chronically treated was with vigabatrin than the other groups. A significantly decrease in the striatal GABA levels was found in acutely and chronically diazepam-treated rats. These findings may suggest that vigabatrin protects rats from development of some of withdrawal symptoms of benzodiazepines