Valproate is a widely used antiepileptic drug with an unknown mechanism of action.
Several neurotransmitter systems are known to be modulated by valproate.
Purpose of the Study:
To investigate the effects of valproate on various neurotransmitter systems.
To elucidate the potential mechanisms underlying valproate's anticonvulsant activity.
Main Methods:
Administration of valproate to rodents and analysis of neurotransmitter levels (serotonin, glycine, GABA, aspartate).
Assessment of valproate's effects on enzyme activity (hepatic glycine cleavage, GABA-T, SSADH).
Evaluation of valproate's impact on neuronal firing and neurotransmitter uptake/release/binding.
Main Results:
Valproate elevated brain serotonin precursor and metabolite levels but anticonvulsant action was preserved after serotonin depletion.
Valproate increased urinary and plasma glycine levels and inhibited hepatic glycine cleavage, but did not affect cerebral glycine levels or action.
Valproate increased brain GABA levels, inhibited GABA-metabolizing enzymes, and augmented GABA's inhibitory neuronal effects. It also decreased cerebral aspartate levels in a dose-dependent manner, correlating with anticonvulsant potency.
Conclusions:
Valproate's anticonvulsant effects are not solely mediated by serotonin.
Valproate's mechanism involves modulation of inhibitory neurotransmitters like GABA and potentially excitatory neurotransmitters like aspartate.
Valproate's multifaceted actions on neurotransmitter systems contribute to its therapeutic efficacy in epilepsy.