Inhibitory effect of glutamate release from rat cerebrocortical nerve terminals by α2 adrenoceptor agonist dexmedetomidine

The present study examined the effect of dexmedetomidine, an α2 adrenoceptor agonist, on endogenous glutamate release in rat cerebral cortex nerve terminals (synaptosomes). We also explored the possible mechanism that triggers dexmedetomidine to act. Dexmedetomidine dose-dependently inhibited the release of glutamate evoked by the K+ channel blocker 4-aminopyridine. Presynaptic α2A adrenoceptors were involved in this release inhibition, with the α2A antagonist (but not by the α2B/C antagonist) blocking the dexmedetomidine-mediated inhibition. The effect of dexmedetomidine on the evoked glutamate release was prevented by the chelating extracellular Ca2+ ions, and by the vesicular transporter inhibitor bafilomycin A1. However, the glutamate transporter inhibitor DL-threo-beta-benzyl-oxyaspartate did not have any effect on the action of dexmedetomidine. Dexmedetomidine decreased the degree of depolarization-induced increase in the intrasynaptosomal Ca2+ levels, but did not affect the synaptosomal membrane potential. The inhibitory effect of dexmedetomidine on evoked glutamate release was abolished by blocking the Cav2.2 (N-type) and Cav2.1 (P/Q-type) channels, but was insensitive to the endoplasmic reticulum ryanodine receptors or mitochondrial Na+/Ca2+ exchange. In addition, the mitogen-activated/extracellular signal-regulated kinase kinase (MEK) inhibitors prevented dexmedetomidine from inhibiting glutamate release. Further, western blotting showed that dexmedetomidine decreased the 4-aminopyridine-induced phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase 1 and 2 and synapsin I, the main presynaptic target of mitogen-activated protein kinase. Thus, we concluded that dexmedetomidine acts at α2A adrenoceptors present on cerebrocortical nerve terminals inhibit the release of glutamate. We further concluded that this effect is linked to the suppression of voltage-dependent Ca2+ channels and mitogen-activated protein kinase activity.