Dexmedetomidine is a highly selective alpha(2)-agonist and reduces norepinephrine release from several neuronal tissues. However, supraclinical concentrations of dexmedetomidine have been reported to increase norepinephrine release from cardiac stores. In addition, some report using microdialysis shows that intrathecal clonidine increased norepinephrine release from the dorsal horn in mid-thoracic spinal cord but dexmedetomidine did not. Thus, in the present study we have studied effects of dexmedetomidine on norepinephrine release from rat cerebrocortical slices and compared this with clonidine. We have also used a selective alpha(2)-antagonist yohimbine and an orexin-1 receptor antagonist SB-334867 to examine whether the effects of dexmedetomidine on norepinephrine release are mediated via alpha(2)-adrenergic or orexin (OX) receptors. In addition, concentrations of orexin A in the evoked sample were also measured. Dexmedetomidine significantly increased norepinephrine release (basal=100%) from rat cerebrocortical slices in a concentration-dependent manner with E(max) 377.3+/-8.6% and pEC(50) 6.12+/-0.07, whereas clonidine significantly reduced the release with E(max) 62.1+/-6.8% and pEC(50) 4.55+/-0.25. Yohimbine (10(-5)M) did not affect the concentration-response curve of dexmedetomidine for norepinephrine release. However, SB-334867 concentration-dependently antagonized dexmedetomidine-evoked norepinephrine release with I(max) 91.0+/-9.4% and pIC(50) 5.99+/-0.18. Orexin A concentrations did not differ between the samples. Thus, supraclinical concentrations of dexmedetomidine increase norepinephrine release from rat cerebrocortical slices, and this release may be mediated via OX(1) but not alpha(2)-adrenoceptors.