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

I 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 botulin um toxins (BoNTs) on basal, Ca2+- and K+-evoked release of dopamine (DA) an d serotonin (5-HT) were determined by microdialysis in the hippocampus of f reely moving rats. 2 Basal release of monoamine was decreased by pre-microinjection of the syn taxin inhibitor, BoNT/C, but only weakly affected by the synaptobrevin inhi bitor, BoNT/B. Ca2+-evoked release was inhibited by BoNT/C selectively. K+- evoked release was reduced by BoNT/B predominantly and BoNT/C weakly, 3 Perfusion with low and high concentrations of CBZ and ZNS increased and d ecreased basal monoamine release, respectively. Perfusion with VPA increase d basal 5-HT release concentration-dependently, whereas basal DA release wa s affected by VPA biphasic concentration-dependently, similar to CBZ and ZN S. This stimulatory action of AEDs on basal release was inhibited by BoNT/C predominantly. 4 Ca2+-evoked monoamine release was increased by low concentrations of CBZ, ZNS and VPA, but decreased by high concentrations. These effects of the AE Ds on Ca2+-evoked release were inhibited by BoNT/C, but not by BoNT/B. 5 K+-evoked monoamine release was reduced by AEDs concentration-dependently . The inhibitory effect of these three AEDs on K+-evoked release was inhibi ted by BoNT/B, but not by BoNT/C, 6 These findings suggest that the therapeutic-relevant concentration of CBZ , VPA and ZNS affects exocytosis of DA and 5-HT, the enhancement of syntaxi n-mediated monoamine release during resting stage, and the inhibition of sy naptobrevin-mediated release during depolarizing stage.