Reduced anticonvulsant efficacy of valproic acid in dopamine beta-hydroxylase knockout mice

Valproic acid (VPA) is a widely used treatment for both epilepsy and bipolar disorders, although its therapeutic mechanism of action is not fully understood. Because norepinephrine (NE) is implicated in seizure susceptibility and affective disorders, and given previous findings indicating that VPA can act on the NE system, it is possible that NE may mediate some of the therapeutic actions of VPA. To test this hypothesis, we measured flurothyl-induced seizure susceptibility and severity parameters after both acute and chronic VPA treatments in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE. We found that the protective effects of acute VPA on seizure susceptibility, as measured by latency to first myoclonic jerk, were attenuated in Dbh -/- mice. Further, while acute VPA reduced the number of control mice that progressed to tonic extension, VPA did not reduce seizure severity in Dbh -/- mice. The carryover anticonvulsant effects following cessation of chronic VPA treatment were similar in both genotypes. Therefore, we conclude that NE is involved in some of the anticonvulsant effects of VPA, especially the effect of acute VPA on seizure severity.