Age-dependence of the anticonvulsant effects of the GABA uptake inhibitor tiagabine in vitro.
Epileptic syndromes frequently start at childhood and therefore it is crucial to test new anticonvulsants at immature stages of the nervous system. We compared the effects of the gamma-aminobutyric acid (GABA) uptake inhibitor tiagabine [(R)-N-(4, 4-bis(3-methyl-2-thienyl)but)3-en-1-yl nipecotic acid] on low-Mg(2+)-induced epileptic discharges in brain slices from rat pups (p 5-8) and juvenile animals (p 15-20). In tissue from rat pups, tiagabine slightly reduced epileptiform activity in hippocampal area CA1 but had no effect in the entorhinal cortex. In juvenile rats, epileptiform discharges were unaffected in CA1 but suppressed by 60% in the entorhinal cortex. While tiagabine increases its efficacy with age, in-situ hybridisation and PCR analysis show that mRNA coding for the neuronal GABA-transporter GAT-1 is already present at p 5. We therefore conclude that the increasing efficacy of tiagabine during ontogenesis is due to functional maturation of GABAergic synapses rather than to up-regulation of GAT-1 expression.
Sabau
A
A
Johannes-Müller-Institut für Physiologie der Charité, Humboldt-Universität zu Berlin, Tucholskystr. 2, 10117, Berlin, Germany.
Frahm
C
C
Pfeiffer
M
M
Breustedt
J
J
Piechotta
A
A
Numberger
M
M
Engel
D
D
Heinemann
U
U
Draguhn
A
A
D000200:Action Potentials / Q000187:drug effects*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D018728:Entorhinal Cortex / Q000187:drug effects / Q000378:metabolism; D004833:Epilepsy, Temporal Lobe / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology*; D050485:GABA Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids / Q000494:pharmacology*; D027361:Organic Anion Transporters; D051381:Rats; D017208:Rats, Wistar; D000078308:Tiagabine
D000927:Anticonvulsants; D002352:Carrier Proteins; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; C493415:Slc6a1 protein, rat; D000078308:Tiagabine