Age-dependence of the anticonvulsant effects of the GABA uptake inhibitor tiagabine in vitro

Epileptic syndromes frequently start at childhood and therefore it is cruci al to test new anticonvulsants at immature stages of the nervous system. We compared the effects of the gamma-aminobutyric acid (GABA) uptake inhibito r tiagabine [(R)-N-(4,4-bis(3-methyl-2-thienyl)but)3-en-1-yl nipecotic acid ] on low-Mg2+-induced epileptic discharges in brain slices from rat pups (p 5-8) and juvenile animals (p 15-20). In tissue from rat pups, tiagabine sl ightly reduced epileptiform activity in hippocampal area CAI but had no eff ect in the entorhinal cortex. In juvenile rats, epileptiforn discharges wer e unaffected in CA1 bur suppressed by 60% in the entorhinal cortex. While t iagabine increases its efficacy with age, in-situ hybridisation and PCR ana lysis show that mRNA coding for the neuronal GABA-transporter GAT-1 is alre ady present at p 5. We therefore conclude that the increasing efficacy of t iagabine during ontogenesis is due to functional maturation of GABAergic sy napses rather than to up-regulation of GAT-1 expression. (C) 1999 Elsevier Science B.V. All rights reserved.