SUBCLASSIFICATION OF PRESYNAPTIC ALPHA(2)-ADRENOCEPTORS - ALPHA(2D)-AUTORECEPTORS IN MOUSE-BRAIN

The study was devised to classify, by means of antagonist affinities, the presynaptic alpha(2)-autoreceptors in mouse cerebral cortex in ter ms of alpha(2A), alpha(2B), alpha(2C) and alpha(2D) A set of antagonis ts was chosen that was able to discriminate between the four subtypes. Slices of the cortex were preincubated with H-3-noradrenaline and the n superfused and stimulated electrically. The stimulation periods used (4 pulses, 100 Hz) did not lead to alpha(2)-autoinhibition as shown b y the lack of an increase by rauwolscine of the evoked overflow of tri tium. The alpha(2)-selective agonists 5-bromo-6-(2-imidazolin-2-ylamin o)-quinoxaline (UK 14,304) and alpha-methylnoradrenaline reduced the e voked overflow. All 10 antagonists shifted the concentration-inhibitio n curve of UK 14,304 to the right. Rauwolscine also shifted the concen tration-inhibition curve of alpha-methylnoradrenaline to the right, pK (d) values of the antagonists were calculated from the shifts. The pK( d) values of rauwolscine against UK 14,304 and alpha-methylnoradrenali ne were very similar (8.0 and 7.9, respectively). Comparison with anta gonist affinities for prototypic native alpha(2) binding sites, alpha( 2) binding sites in cells transfected with alpha(2) subtype genes, and previously classified presynaptic alpha(2)-adrenoceptors - all taken from the literature - indicates that the alpha(2)-autoreceptors in mou se brain cortex are alpha(2D). This is the first subtype determination of alpha(2)-autoreceptors in the mouse. It supports the hypothesis th at at least the majority of alpha(2)-autoreceptors belong to the alpha (2A/D) branch of the alpha(2)-adrenoceptor tree.