Biphasic actions of topiramate on monoamine exocytosis associated with both soluble N-ethylmaleimide-sensitive factor attachment protein receptors and Ca2+-induced Ca2+-releasing systems

• DOI: 10.1016/j.neuroscience.2005.03.045
• Publication Date: 2005-06-15T11:43:59Z
• Authors: M. Okada; S. Yoshida; G. Zhu; S. Hirose; S. Kaneko
• Keywords: Male; Botulinum Toxins; Macrocyclic Compounds; Dose-Response Relationship, Drug; Microdialysis; Blotting, Western; Fructose; Exocytosis; Rats; 03 medical and health sciences; Neuroprotective Agents; 0302 clinical medicine; Ethylmaleimide; Potassium; Animals; Biogenic Monoamines; Calcium; Enzyme Inhibitors; Rats, Wistar; N-Ethylmaleimide-Sensitive Proteins; Oxazoles; Chromatography, High Pressure Liquid

To explore the pharmacological mechanisms of topiramate (TPM), we determined the effects of TPM on monoamine (dopamine and serotonin) exocytosis associated with N-ethylmaleimide-sensitive factor attachment protein receptors and Ca(2+)-induced Ca(2+)-releasing systems, including inositol-triphosphate receptor and ryanodine receptor in freely moving rat pre-frontal cortex using in vivo microdialysis. During resting stage, Ca(2+) output from endoplasmic reticulum Ca(2+) store via inositol-triphosphate receptor regulates syntaxin-associated monoamine exocytosis mechanism, whereas during neuronal hyperexcitable stage, Ca(2+) output via ryanodine receptor regulates synaptobrevin-associated monoamine exocytosis mechanism. Basal monoamine releases were increased and decreased by therapeutically relevant and supratherapeutic concentration of TPM, respectively. The therapeutic-relevant concentration of TPM increased Ca(2+)-evoked release concentration-dependently; however, its stimulatory effect was attenuated in the supratherapeutic range. The K(+)-evoked releases were reduced by TPM concentration-dependently (from therapeutic to supratherapeutic ranges). The therapeutic-relevant concentration of TPM-induced elevation of basal release was reduced by cleavage with syntaxin and inhibition of inositol-triphosphate receptor predominantly, by cleavage with SNAP-25 and synaptobrevin weakly, but not by ryanodine receptor inhibitor. The therapeutic-relevant concentration of TPM-induced elevation of Ca(2+)-evoked release was reduced by cleavage with syntaxin and inositol-triphosphate receptor inhibitor selectively. The therapeutic-relevant concentration of TPM-induced reduction of K(+)-evoked monoamine release was abolished by cleavage with synaptobrevin, but was not affected by cleavage with SNAP-25 or synaptobrevin. The stimulatory effect of ryanodine receptor agonist on K(+)-evoked monoamine release was reduced by TPM, whereas that of inositol-triphosphate receptor agonist was not affected by TPM. Therefore, these results indicate that the combination of the effects of TPM on exocytosis mechanisms associated with SNARE and Ca(2+)-induced Ca(2+)-releasing systems, enhancement of inositol-triphosphate receptor/syntaxin and inhibition of ryanodine receptor/synaptobrevin in pre-frontal cortex, may be involved in clinical actions of TPM.