Tiagabine is a novel antiepileptic drug which has clinical efficacy against complex refractory and myoclonic seizures. The anticonvulsant mechanism of action of tiagabine results from its blockade of neuronal and glial GABA-uptake, thereby increasing GABA levels in the synaptic cleft. Here we present a comparison of the preclinical anticonvulsant profile of tiagabine with that of lamotrigine, gabapentin and vigabatrin in the following tests (all antiepileptic drugs were administered i.p.): seizures induced by pentylentetrazol (PTZ), 6,7-dimethoxy-4-ethyl-b-carboline-3-carboxylate (DMCM) and maximal electroshock (MES); sound induced seizures in DBA/2 mice and finally acute amygdala kindled seizures. Tiagabine was the most potent drug in antagonizing tonic convulsions induced by PTZ, DMCM and sound induced seizures in DBA/2 mice with ED50 values of 2, 2 and 1 mumol/kg, respectively, followed by lamotrigine with ED50 values of 9, 43 and 6 mumol/kg, respectively. Gabapentin and vigabatrin had ED50 values in the same tests of 185, 452, 66 mumol/kg and 2322, > 7740, 3883 mumol/kg, respectively. Tiagabine was the only drug capable of blocking PTZ-induced clonic convulsions (ED50 = 5 mumol/kg), an effect seen at low but not high doses of tiagabine. Lamotrigine was the only drug which antagonized tonic convulsions in the MES test (ED50 = 36 mumol/kg). Therapeutic index (TI) of antiepileptic drugs in NMRI- and DBA/2-mice ranked with decreasing TI lamotrigine > gabapentin > vigabatrin > tiagabine. All drugs reduced the generalized seizures in amygdala kindled rats, but tiagabine and gabapentin furthermore attenuated afterdischarge duration of amygdala kindled seizures. However, an ED50 value against amygdala kindled focal seizures was only obtained for tiagabine (36 mumol/kg). The data here presented show that tiagabine, lamotrigine, gabapentin and vigabatrin possess different preclinical anticonvulsant profiles which is of relevance to the clinical anticonvulsant profiles of the drugs.