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Neuropharmacology. 2009 Sep;57(3):322-31. doi: 10.1016/j.neuropharm.2009.05.005. Epub 2009 May 29.

Zonisamide enhances delta receptor-associated neurotransmitter release in striato-pallidal pathway.

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  • 1Department of Psychiatry, Division of Neuroscience, Graduate School of Medicine, Mie University, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.


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.

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