HISTAMINE-H3A RECEPTOR-MEDIATED INHIBITION OF NORADRENALINE RELEASE IN THE MOUSE-BRAIN CORTEX

Mouse brain cortex slices preincubated with H-3-noradrenaline were superfused with physiological salt solution containing desipramine plus a drug with alpha-2-adrenoceptor antagonist properties, and the effects of histamine receptor ligands on the electrically (0.3 Hz) evoked tritium overflow were studied. The evoked overflow (from slices superfused with phentolamine) was inhibited by histamine (pIC35 6.53), the H-3 receptor agonist R-(-)-alpha-methylhistamine (7.47) and its S-(+)-enantiomer (5.82) but not influenced by the H-1 receptor agonist 2-(2-thiazolyl)-ethylamine 3.2-mu-mol/l and the H-2 receptor agonist dimaprit 10-mu-mol/l. The inhibitory effect of histamine was not affected by the H-1 receptor antagonist dimetindene 1-mu-mol/l and the H-2 receptor antagonist ranitidine 10-mu-mol/l. The concentration-response curve of histamine (determined in the presence of rauwolscine) was shifted to the right by the H-3 receptor antagonists thioperamide (apparent pA2 8.67), impromidine (7.30) and burimamide (6.82) as well as by dimaprit (6.16). The pA2 values of the four drugs were compared with their affinities for H-3A and H-3B binding sites in rat brain membranes (West et al. 1990 Mol Pharmacol 38:610); a significant correlation was obtained for the H-3A, but not for the H-3B sites. The results suggest that noradrenaline release in the mouse brain cortex is inhibited by histamine via H-3A receptors and that dimaprit is an H-3 receptor antagonist of moderate potency.