THE GAMMA-AMINOBUTYRIC-ACID UPTAKE INHIBITOR, TIAGABINE, IS ANTICONVULSANT IN 2 ANIMAL-MODELS OF REFLEX EPILEPSY

The effects of i.p. administration of the gamma-aminobutyric acid (GAB A) uptake inhibitors R(-)N-(4,4-di(3-methylthien-2-yl)-but-3-enyl) nip ecotic acid hydrochloride (tiagabine; molecular weight 412.0), oxy)eth yl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-71 1; molecular weight 386.9), and (+/-)-nipecotic acid (molecular weight 128.2) are compared with those of carbamazepine (molecular weight 236 .3) on sound-induced seizures and locomotor performance in genetically epilepsy-prone (GEP) rats. The ED(50) value against clonic seizures ( in mu mol kg(-1) at the time of maximal anticonvulsant effect) for tia gabine was 23 (0.5 h), and for NNC-711 was 72 (1 h), and for carbamaze pine was 98 (2 h). (+/-)-Nipecotic acid (0.4-15.6 mmol kg(-1)) was not anticonvulsant. High doses of NNC-711 (207-310 mu mol kg(-1)) and of (+/-)-nipecotic acid (39-78 mmol kg(-1)) induced ataxia and myoclonic seizures 0.25-1 h. Tiagabine and carbamazepine did not induce myocloni c seizures and had similar therapeutic indices (locomotor deficit ED(5 0)/anticonvulsant ED(50)) ranging from 0.4 to 1.9. In Papio papio, we observed a reduction in photically induced myoclonic seizures with tia gabine (2.4 mu mol kg(-1) i.v.) accompanied with neurological impairme nt. Tiagabine has comparable anticonvulsant action to carbamazepine in rats and has anticonvulsant effects in non-human primates supporting the potential use of inhibitors of GABA uptake as therapy for epilepsy .