ACTION OF DEXMEDETOMIDINE ON RAT LOCUS-COERULEUS NEURONS - INTRACELLULAR-RECORDING IN-VITRO

The action of dexmedetomidine on rat locus coeruleus neurones was exam ined using intracellular recordings from the in vitro brain slice prep aration. Concentrations of dexmedetomidine from 1 to 1000 nM were test ed. At 30 nM, dexmedetomidine produced complete inhibition of firing o f all neurones tested (n = 21); this was associated with a 13 mV hyper polarization (range 2.2-29.7 mV, n = 21) and a 27% reduction in input resistance (range 11.1-46.2%, n = 17). The dexmedetomidine responses r eached a plateau phase between 100 and 1000 nM. Based on single-cell r ecordings, the hyperpolarizing potency of dexmedetomidine was found to be 6 times greater than that of clonidine (n = 10). The reversal pote ntial for the dexmedetomidine-induced hyperpolarization was -106.9 +/- 1.7 mV (n = 9), a value similar to the K+ equilibrium potential; hype rpolarization was blocked by both CsCl and BaCl2. The effect of dexmed etomidine was antagonized by yohimbine, with a dissociation equilibriu m constant of 30 nM. In contrast, prazosin, the alpha 1-, alpha(2B)- a nd alpha(2C)-adrenoceptor subtype-preferring ligand, did not inhibit t he dexmedetomidine effect. Our results also show that low concentratio ns of oxymetazoline (10-300 nM), an alpha(2A)-adrenoceptor subtype-sel ective drug, cause profound inhibition of neuronal activity in the loc us coeruleus. These data therefore suggest that dexmedetomidine binds to alpha(2A)-adrenoceptors on the cell membrane of neurones of the loc us coeruleus and that this leads to opening of the inwardly rectifying K+ channels, resulting in the observed hyperpolarization of the membr ane.