Effects of histamine H3-receptor ligands on various biochemical indices of histaminergic neuron activity in rat brain

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Abstract

The interaction of the potent histamine H3-receptor ligands i.e. (R)α-methylhistamine, an agonist, and thioperamide, an antagonist, with the three classes of cerebral histamine receptors was studied in vitro and in vivo. The histamine-induced stimulation of 3',5'-cyclic AMP accumulation in slices of the guinea-pig hippocampus was not modified by thioperamide (up to 0.1 mM) and (R)α-methylhiistamine stimulated cyclic AMP accumulation only at millimolar concentrations. Hence, both (R)α-methylhistamine and thioperamide were at least 100 000-fold more potent at H3- than at H1- or H2-receptors in brain. In vivo, the turnover of histamine in rat cerebral cortex, as determined from its depletion elicited by α-fluoromethylhistidine in a synaptosomal fraction was not nmodified by mepyramine and zolantidine but was markiedly enhanced by thioperamide at a (ED50 = 2 mg/kg). Thiopermide also elicited a long-lasting decrease in synaptosomal histamine and increase radioimmunoassayable Nτ-methylhistamine. In contrast, (R)α-methylhistamine markedley reduced cortical [3H]histamine synthesis (ED50 = 5 mg/kg). This long-lasting action was accompanied by an increase in synaptosomal histamine and a decrease in Nτ-methylahistamine levels. These changes were compared with those in plasma drug levels. Hence the two H3-receptor ligands appear to modify the activity of cerebral histamine neurons markedly and in a long-lasting and opposite manner.

References (35)

  • J.M. Arrang et al.

    Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor

    Nature

    (1983)
  • M. Baba et al.

    Effects of halothane, enflurane and pentobarbital brain histamine dynamics in mice

    Naunyn-Schmiedeb. Arch. Pharmacol.

    (1987)
  • B.L. Brown et al.

    A simple and sensitie saturation assay method for the measurement of adrenosine 3':5'-cyclic monophosphate

    Biochem. J.

    (1971)
  • C.R. Calcutt et al.

    Zolantidine (SK&F 95282) is a potent selective brain penetrating histamine H2-receptor antagonist

    Br. J. Pharmacol.

    (1988)
  • A. Carlsson et al.

    Regulation of monoamine metabolism in the central nervous system

    Pharmacol. Rev.

    (1972)
  • O. Curet et al.

    Evidence for the involvement of presynaptic alpha 2 adrenoceptors in the regulation of norepinephrine metabolism in the rat brain

    J. Pharmacol. Exp. Ther.

    (1987)
  • M. Garbarg et al.

    Inhibition of histamine synthesis in brain by α-fluoromethylhistidine, a new irreversible inhibitor in vitro and in vivo studies

    J. Neurochem.

    (1980)
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