Valproate and its major metabolite E-2-en-valproate induce different effects on behaviour and brain monoamine metabolism in rats

Abstract The antiepileptic drug valproate has previously been shown to increase serotonin and dopamine turnover in certain brain regions, but the role of these alterations in the diverse pharmacodynamic effects of valproate is not known. For instance, monoamines have been implicated in the ‘wet dog’ shake behaviour induced by valproate in rats. E-2-en-valproate, a major metabolite of valproate, exhibits the same profile and potency of anticonvulsant activity as valproate, but does not induce wet dog shakes in rats. When administered at about equipotent anticonvulsant doses, both valproate and E-2-en-valproate increased serotonin metabolism in several brain regions of rats, although wet dog shakes were only seen after valproate, thus indicating that wet dog shake behaviour in response to valproate is not mediated by alterations in serotonin. Dopamine metabolism was differentially altered by the two compounds, with marked increases in 3,4-dihydroxyphenylacetic acid or homovanillic acid seen in frontal cortex and brainstem after valproate but not E-2-en-valproate, while the latter drug but not valproate significantly increased 3,4-dihydroxyphenylacetic acid in the amygdala. Levels of noradrenaline were not significantly altered in any of the 8 brain regions examined.