Lack of tolerance to the anticonvulsant effects of tiagabine following chronic (21 day) treatment.

The anticonvulsant, and side effect, profile of the gamma-aminobutyric acid (GABA) uptake inhibitor (R)-N-(4,4-di-(3-methylthien-2-yl)but-3-enyl) nipecotic acid hydrochloride (tiagabine) was examined in mice following chronic (21 day) administration. Twenty-four hours following the discontinuation of the 21 days' treatment with twice daily administration of vehicle or tiagabine at 15 or 30 mg/kg p.o., an ED50 for tiagabine was determined for the anticonvulsant effect, the rotarod performance, the traction response and the inhibition of locomotor activity in the animals treated with vehicle only, and in the groups previously treated with 15 or 30 mg/kg p.o. of tiagabine. There was no significant decrease in the anticonvulsant efficacy of acutely administered tiagabine (ED50 for inhibition of methyl 6,7-dimethoxy-4-ethyl-beta-carboline-2-carboxylate (DMCM)-induced seizures of 1.7 +/- 0.4, 1.9 +/- 0.3, and 2.0 +/- 0.50 mg/kg i.p., respectively). However, there was a significant decrease in the ability of acutely administered tiagabine to impair rotarod performance (ED50 of 5.9 +/- 1.2, 14 +/- 1.9 and 21 +/- 2.7 mg/kg i.p., respectively), inhibit a traction response (ED50 of 10 +/- 1.6, 23 +/- 3.0 and 34 +/- 4.6 mg/kg i.p., respectively), and to inhibit exploratory locomotor activity (ED50 of 13 +/- 23, 19 +/- 2.6 and 28 +/- 38 mg/kg i.p. respectively). Following the discontinuation of chronic tiagabine administration there was no change in pentylenetetrazol (PTZ) seizure threshold, animal weight or gross behavior, suggesting the lack of a behavioral withdrawal syndrome. The production of tolerance to the sedative and ataxic effects, but not the anticonvulsant effects, of tiagabine suggests that tiagabine may be a useful agent for the long-term treatment of epilepsy.