Determination of effects of antiepileptic drugs on SNAREs‐mediated hippocampal monoamine release using in vivo microdialysis

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Abstract
To elucidate possible mechanisms underlying the effects of carbamazepine (CBZ), valproate (VPA) and zonisamide (ZNS) on neurotransmitter exocytosis, the interaction between these three antiepileptic drugs (AEDs) and botulinum toxins (BoNTs) on basal, Ca2+‐ and K+‐evoked release of dopamine (DA) and serotonin (5‐HT) were determined by microdialysis in the hippocampus of freely moving rats. Basal release of monoamine was decreased by pre‐microinjection of the syntaxin inhibitor, BoNT/C, but only weakly affected by the synaptobrevin inhibitor, BoNT/B. Ca2+‐evoked release was inhibited by BoNT/C selectively. K+‐evoked release was reduced by BoNT/B predominantly and BoNT/C weakly. Perfusion with low and high concentrations of CBZ and ZNS increased and decreased basal monoamine release, respectively. Perfusion with VPA increased basal 5‐HT release concentration‐dependently, whereas basal DA release was affected by VPA biphasic concentration‐dependently, similar to CBZ and ZNS. This stimulatory action of AEDs on basal release was inhibited by BoNT/C predominantly. Ca2+‐evoked monoamine release was increased by low concentrations of CBZ, ZNS and VPA, but decreased by high concentrations. These effects of the AEDs on Ca2+‐evoked release were inhibited by BoNT/C, but not by BoNT/B. K+‐evoked monoamine release was reduced by AEDs concentration‐dependently. The inhibitory effect of these three AEDs on K+‐evoked release was inhibited by BoNT/B, but not by BoNT/C, These findings suggest that the therapeutic‐relevant concentration of CBZ, VPA and ZNS affects exocytosis of DA and 5‐HT, the enhancement of syntaxin‐mediated monoamine release during resting stage, and the inhibition of synaptobrevin‐mediated release during depolarizing stage. British Journal of Pharmacology (2001) 134, 507–520; doi:10.1038/sj.bjp.0704285