Development of tolerance to the anticonvulsant effect of GABAmimetic drugs in genetically epilepsy-prone gerbils.

Three drugs which increase GABA-mediated inhibitory neurotransmission in the brain, namely the GABA degradation inhibitors aminooxyacetic acid (AOAA) and gamma-acetylenic GABA (GAG), and the GABA receptor agonist THIP (gaboxadol), were administered to epilepsy-prone gerbils via subcutaneously implanted osmotic minipumps for 2 weeks. The antiepileptic drugs valproic acid (VPA) and diazepam were also included in the experiments. After one day of constant rate application, all GABAmimetics markedly suppressed seizure activity induced in the gerbils by air blast stimulation, but anticonvulsant efficacy of the drugs was lost after 8 and 14 days of treatment. With VPA, only moderate anticonvulsant effects were found because only sub-therapeutic drug levels (about 40 micrograms/ml plasma) were reached via minipump administration. The experiments with diazepam could only be evaluated in part because of instability of the drug in aqueous solution. Determination of brain GABA metabolism in the gerbils indicated that reduction of GABA synthesis may be responsible, at least in part, for development of tolerance to the anticonvulsant effects of AOAA and GAG.