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 autonomic nervous system (heteroreceptors). H-3 heteroreceptors, most probably located on the postganglionic sympathetic nerve fibres innervating the resistance vessels and the heart, have been identified in the model of the pithed rat. Furthermore, we could show in superfusion experiments that H-3 heteroreceptors also occur on the sympathetic neurones supplying the human saphenous vein and the vasculature of the pig retina and on the serotoninergic, dopaminergic and noradrenergic neurones in the brain of various mammalian species, including man. The effects of three recently described H-3 receptor ligands were studied in superfused mouse brain cortex slices. The potency of the novel H-3 receptor agonist imetit exceeded that of R-(-)-alpha-methylhistamine (the reference H-3 receptor agonist) by one log unit and that of histamine by 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 pA2 of the reference H-3 receptor antagonist thioperamide by one log unit). The irreversible antagonism of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was also studied. Interactions of the H-3 heteroreceptor with the dopamine autoreceptor in mouse striatal slices and the alpha2-autoreceptor in mouse brain cortex slices could be demonstrated. Activation of alpha2-autoreceptors decreases the H-3 receptor-mediated effect. Blockade of alpha2-autoreceptors increases the H-3 receptor-mediated effect only if the alpha2-autoreceptors are simultaneously activated by endogenous noradrenaline. The H-3 receptor-mediated inhibition of noradrenaline release in mouse brain cortex slices was attenuated by the K+ channel blocker tetraethylammonium but this attenuation was abolished by reduction of the Ca2+ concentration in the medium (to compensate for the facilitatory effect of tetraethylammonium on noradrenaline release). Accordingly, we assume that the H-3 receptors are not coupled to voltage-sensitive K+ channels. Pertussis toxin and N-ethylmaleimide attenuated the H-3 receptor-mediated effect in the mouse brain cortex, suggesting that the H-3 receptors are coupled to a G protein (eg G(i) or G(o)). However, negative coupling to an adenylate cyclase does not appear to exist since an H-3 receptor-mediated inhibition of cAMP accumulation was not obtained in mouse brain cortex membranes. H-3 receptor ligands are currently undergoing clinical testing and might become new remedies for the treatment of diseases of the gastrointestinal and bronchial system and the CNS.