MODULATION OF NEUROTRANSMITTER RELEASE VIA HISTAMINE H-3 HETERORECEPTORS

Presynaptic H-3 receptors occur on histaminergic neurones of the CNS ( autoreceptors) and on non-histaminergic neurones of the central and au tonomic nervous system (heteroreceptors). H-3 heteroreceptors, most pr obably located on the postganglionic sympathetic nerve fibres innervat ing the resistance vessels and the heart, have been identified in the model of the pithed rat. Furthermore, we could show in superfusion exp eriments that H-3 heteroreceptors also occur on the sympathetic neuron es supplying the human saphenous vein and the vasculature of the pig r etina and on the serotoninergic, dopaminergic and noradrenergic neuron es in the brain of various mammalian species, including man. The effec ts of three recently described H-3 receptor ligands were studied in su perfused mouse brain cortex slices. The potency of the novel H-3 recep tor agonist imetit exceeded that of R-(-)-alpha-methylhistamine (the r eference H-3 receptor agonist) by one log unit and that of histamine b y almost two log units. Clobenpropit was shown to be a competitive H-3 receptor antagonist, exhibiting a pA2 as high as 9.6 (exceeding the p A2 of the reference H-3 receptor antagonist thioperamide by one log un it). The irreversible antagonism of N-ethoxycarbonyl-2-ethoxy-1,2-dihy droquinoline (EEDQ) was also studied. Interactions of the H-3 heterore ceptor with the dopamine autoreceptor in mouse striatal slices and the alpha2-autoreceptor in mouse brain cortex slices could be demonstrate d. Activation of alpha2-autoreceptors decreases the H-3 receptor-media ted effect. Blockade of alpha2-autoreceptors increases the H-3 recepto r-mediated effect only if the alpha2-autoreceptors are simultaneously activated by endogenous noradrenaline. The H-3 receptor-mediated inhib ition of noradrenaline release in mouse brain cortex slices was attenu ated by the K+ channel blocker tetraethylammonium but this attenuation was abolished by reduction of the Ca2+ concentration in the medium (t o compensate for the facilitatory effect of tetraethylammonium on nora drenaline release). Accordingly, we assume that the H-3 receptors are not coupled to voltage-sensitive K+ channels. Pertussis toxin and N-et hylmaleimide attenuated the H-3 receptor-mediated effect in the mouse brain cortex, suggesting that the H-3 receptors are coupled to a G pro tein (eg G(i) or G(o)). However, negative coupling to an adenylate cyc lase does not appear to exist since an H-3 receptor-mediated inhibitio n of cAMP accumulation was not obtained in mouse brain cortex membrane s. H-3 receptor ligands are currently undergoing clinical testing and might become new remedies for the treatment of diseases of the gastroi ntestinal and bronchial system and the CNS.