Subclassification of release‐regulating α2‐autoreceptors in human brain cortex

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Abstract
1 Release-regulating α2-autoreceptors in human brain were characterized pharmacologically in cortical slices from patients undergoing neurosurgery to remove subcortical tumours; the slices were prelabelled with [3H]-noradrenaline ([3H]-NA) and stimulated electrically (3 Hz, 2 ms, 24 mA) under superfusion conditions. 2 The stimulus-evoked tritium overflow was almost totally Ca2+-dependent and tetrodotoxin-sensitive. 3 Clonidine and oxymetazoline 0.01 to 1 μm inhibited in a concentration-dependent manner the evoked overflow of tritium. The two drugs were equipotent (EC50 = 0.03 μm) and their maximal effect was approx. 45%. Phenylephrine and methoxamine, up to 1 μm, did not affect tritium overflow. 4 Yohimbine (0.01–0.1 μm) shifted the concentration-response curve of clonidine to the right. The calculated pA2 value was 8.29. 5 Prazosin and 2-[2-[4-(o-methoxyphenyl)piperazine-1-yl]ethyl]-4,4-dimethyl-1,3(2H,4H)-isoquinolinedione (AR-C 239), tested at 0.3 μm, did not modify the concentration-response curve of clonidine. 6 The effect of clonidine was antagonized by (+)-mianserin (pA2 = 7.74), but not by up to 0.3 μm of the (−)-enantiomer. The concentration-response curve of clonidine was shifted to the right by the novel α2-adrenoceptor antagonist, 5-chloro-4-(1-butyl-1,2,5,6-tetrahydropyridin-3-yl)-thiazole-2-amine (Z)-2-butenedioate (1:1) salt (ORG 20350) (pA2 = 7.55). 7 Yohimbine, (+)-mianserin and ORG 20350, but not prazosin and (−)-mianserin, increased the electrically-evoked tritium overflow, suggesting that autoreceptors may be tonically activated by endogenous NA. 8 Desipramine (1 μm) increased evoked tritium overflow from human cortex slices. The effect of clonidine (0.01 − 1 μm) on the evoked overflow of tritium was reduced in presence of 1 μm desipramine. 9 It is proposed that autoregulation of NA release can occur in human cerebral cortex. The process involves activation of α2-adrenoceptors which may be either the α2A or the α2D subtype.