H-2 RECEPTOR-MEDIATED FACILITATION AND H-3 RECEPTOR-MEDIATED INHIBITION OF NORADRENALINE RELEASE IN THE GUINEA-PIG BRAIN

The effect of histamine and related drugs on the tritium overflow evok ed electrically (0.3 Hz) or by introduction of Ca2+ ions into Ca2+-fre e K+-rich (25 mmol/l) medium containing tetrodotoxin was studied in su perfused guinea-pig brain cortex, cerebellum, hippocampus or hypothala mus slices and in mouse brain cortex slices preincubated with H-3-nora drenaline. The electrically evoked tritium overflow in guinea-pig cort ex slices was inhibited by histamine; the H-3 receptor antagonist clob enpropit reversed the effect of histamine to a slight facilitation, Th e facilitatory effect of histamine (obtained in the presence of cloben propit) was not affected by the H-1 receptor antagonist mepyramine but abolished by the H-2 receptor antagonist ranitidine. In the absence o f clobenpropit, ranitidine augmented the inhibitory effect of histamin e. In slices superfused in the presence of ranitidine, the evoked over flow was inhibited by histamine and, more potently, by the H-3 recepto r agonist R-alpha-methylhistamine in a concentration-dependent manner (maximum inhibitory effect obtained for both agonists 30-35%). The con centration-response curve of histamine was shifted to the right by the H-3 receptor antagonist thioperamide. R-alpha-Methylhistamine inhibit ed the electrically evoked tritium overflow also in guinea-pig cerebel lar, hippocampal and hypothalamic slices. In cortex slices superfused in the presence of clobenpropit, the H-2 receptor agonists impromidine and, less potently, R-sopromidine facilitated the evoked overflow in a concentration-dependent manner. S-Sopromidine only tended to increas e the evoked overflow. The effect of impromidine was counteracted by t he H-2 receptor antagonists ranitidine and cimetidine. The extent of t he maximum facilitatory effect of impromidine (by 15-20%) was about th e same when (i) the Ca2+ concentration in the medium was reduced from 1.3 to 0.98 mmol/l, (ii) the time of exposure to impromidine was reduc ed from 28 to 8 min or (iii) cerebellar, hippocampal or hypothalamic s lices were used instead of cortical slices. The Ca2+-induced tritium o verflow in guinea-pig cortex slices was inhibited by histamine (in the presence of ranitidine); this effect was abolished by cloben-propit. In slices superfused in the presence of clobenpropit, impromidine fail ed to facilitate the Ca2+-evoked tritium overflow. The electrically ev oked tritium overflow in mouse brain cortex slices was inhibited by hi stamine by about 60% (both in the absence or presence of ranitidine). The inhibitory effect of histamine was abolished (but not reversed) by clobenpropit. In conclusion, noradrenaline release in the guinea-pie brain carter is inhibited via presynaptic H-3 receptors and facilitate d via H-2 receptors not located presynaptically. In the mouse brain co lter, only inhibitory H-3 receptors occur. The extent of the H-3 recep tor-mediated effect is more marked in the mouse than in the guinea-pig brain cortex.