SUBTYPE-SPECIFICITY OF THE PRESYNAPTIC ALPHA(2)-ADRENOCEPTORS MODULATING HIPPOCAMPAL NOREPINEPHRINE RELEASE IN RAT

In vivo brain microdialysis and high-performance liquid chromatography with electrochemical detection were used to study the effect of different selective alpha(2)-antagonists on hippocampal norepinephrine (NE) release in freely moving awake rat. Systemic administration (0.5 mg/kg i.p.) of either the alpha(2AD)-antagonist BRL 44408 or the alpha(2BC)-antagonist ARC 239 did not significantly change the basal release of NE. At a higher dose (5 mg/kg i.p.) ARC 239 was still ineffective, whereas BRL 44408 caused a significant increase of the extracellular level of NE. Similar results were obtained from in vitro perfusion experiments. Rat hippocampal slices were loaded with [H-3]NE and the electrical stimulation-evoked release of [H-3]NE was determined. The alpha(2)-antagonists were applied in a concentration range of 10(-8) to 10(-6) M. ARC 239 was ineffective, whereas BRL 44408 significantly increased the electrically induced release of [H-3]NE. In agreement with the data of microdialysis and perfusion experiments, BRL 44408 displaced [H-3]yohimbine from hippocampal and cortical membranes of rat brain with high affinity whereas ARC 239 was less effective. The pK(i) values of eight different alpha(2)-adrenergic compounds showed a very good correlation (r = 0.98, slope = 1.11 P < 0.0001) in hippocampus and frontal cortex where the alpha(2)-adrenoceptors have been characterized as alpha(2D)-subtype. Our data indicate that hippocampal NE release in rat is regulated by alpha(2D)-adrenoceptors, a species variation of the human alpha(2A)-subtype.