A recent randomized control study demonstrated that
zonisamide (ZNS), an
antiepileptic drug, is effective in
Parkinson's disease at the lower than the therapeutic doses against
epilepsy (25-50 mg/day); however, the detailed mechanism of antiparkinsonian effects of ZNS remains to be clarified. To determine the mechanism of antiparkinsonian effect of ZNS, we investigated the effects of ZNS on extracellular levels of
dopamine in the striatum (STR),
glutamate in substantia nigra pars reticulata (SNr),
GABA in globus pallidus (GP), subthalamic nucleus (STN) and SNr, using multiple microdialysis probes. Striatal perfusion of 1000 microM ZNS (within therapeutic-relevant concentration against
epilepsy) increased extracellular levels of
dopamine in STR, whereas 100 microM ZNS (lower than the therapeutic-relevant concentration against
epilepsy but within the therapeutic rage against
Parkinson's disease) did not affect it. Striatal perfusion of ZNS (100 and 1000 microM) decreased the extracellular levels of
GABA in STN and
glutamate in SNr, but decreased extracellular
GABA level in GP without affecting
GABA level in SNr. These concentration-dependent effects of ZNS on extracellular
neurotransmitter levels were independent of
dopamine and delta(2) receptors; however, blockade of delta(1) receptor inhibited the effects of ZNS. Furthermore, activation of delta(1) receptor enhanced the effects of ZNS on
neurotransmitter level. These results suggest that ZNS does not affect the direct pathway but inhibits the indirect pathway, which is mediated by delta(1) receptor. Therefore, the antiparkinsonian effects of ZNS seem to be mediated through the interaction between lower than therapeutically-relevant concentration against
epilepsy of ZNS (100 microM) and delta(1) receptor.