Anticonvulsant activity of pregabalin in the maximal electroshock-induced seizure assay in α2δ1 (R217A) and α2δ2 (R279A) mouse mutants

Two targeted mouse mutants have been made in which either the α2δ1 subunit was mutated (arginine-to-alanine mutation at amino acid 217; R217A) or the α2δ2 subunit was mutated (arginine-to-alanine mutation at amino acid 279; R279A). These mutations in α2δ1 or α2δ2 render the subunits relatively insensitive to pregabalin binding. The anticonvulsant activity of pregabalin was assessed in these different mouse lines using the maximal electroshock-induced seizure (MES) model. Pregabalin reduced the percentage of seizures and increased the latency to seizure in the MES model in two parental mouse strains used to construct the mutants. Pregabalin also reduced the percentage of seizures and increased latency to seizure similarly in the α2δ2 (R279A) and WT littermate control mice. In contrast, pregabalin's anticonvulsant efficacy was significantly reduced in α2δ1 (R217A) mutants compared with WT littermate control mice. Phenytoin showed anticonvulsant activity across all WT and mutant mice. These data show that the anticonvulsant activity of pregabalin in the MES model requires binding to the α2δ1 subunit.