Participation of gaba-ergic system in the development of tolerance to action of topiramate and lamotrigine

The aim of the research was to examine changes in the functioning of the GABA-ergic system system of the brain that lead to tolerance to the action of anticonvulsant drugs of new generation. Experiments were conducted on the nonlinear white mice, weighing 18-20 g and white rats, weighing 180-200 g. The study anticonvulsants included lamotrigine, 30 mg/kg, topiramate, 300 mg/kg. The drugs are administered intraperitoneally 1 h before the experiment. The anticonvulsants were used daily for 14 days to form tolerance to these drugs. Influence of anticonvulsant drugs such as topiramate and lamotrigine on the inhibitory neurotransmitter GABA-ergic system was studied on intolerant and tolerant animals to the action of these drugs. There was compared the impact of studied anticonvulsants drugs on the effects of the thiosemicarbazide in a dose of 20 mg/kg intraperitoneally. There was determined the GABA content in the left and right hemispheres of the animal brain using thin layer chromatography. Topiramate administration to white mice prevents the development of thiosemicarbazide-induced convulsion in 100 % cases, and lamotrigine do in 60 % out of 100 % cases. Anticonvulsant activity of topiramate administrated to tolerant animals is not shown. The development of thiosemicarbazide-induced convulsion has been observed in 75 % of animal tolerant to action of lamotrigine. The anticonvulsants drugs investigated increase levels of GABA significantly 1 h after administration in the brain tissue of white rats. Topiramate and lamotrigine have a dominant effect on the right hemisphere of the brain. Levels of GABA in brain tissues were not significantly different in intact animals (control group) and animals tolerant to the action as topiramate and lamotrigine. The data obtained indicate that specific effects of selective antagonist of GABA-ergic brain system thiosemicarbazide change under the influence of anticonvulsants topiramate and lamotrigine. Antagonistic action of these drugs disappears against the thiosemicarbazide when it was forming tolerance to the studied anticonvulsants. Topiramate and lamotrigine activate a pool of GABA in brain tissues. These anticonvulsants drugs increase brain GABA levels primarily in the right hemisphere. It was found that GABA-ergic synaptic transmission in the neurons of the central nervous system is involved in the mechanisms of tolerance to the action of anticonvulsant drugs.