DEXMEDETOMIDINE SYNERGISM WITH MIDAZOLAM IN THE ELEVATED PLUS-MAZE TEST IN RATS

The anxiolytic profile of dexmedetomidine, a novel, highly-selective alpha(2)-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1-10-mu-g/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1-10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5-mu-g/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an alpha(2)-adrenergic antagonist, atipamezole, 10-50-mu-g/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the alpha(1)-adrenergic antagonist, prazosin, 0.1-10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and alpha(2)-agonist responses do not share any molecular component, there does appear to be "crosstalk" between these two systems. These may involve GABA or noradrenergic "downstream" effects of either dexmedetomidine or midazolam, respectively.