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

Eur J Pharmacol. 1989 May 2;164(1):1-11. doi: 10.1016/0014-2999(89)90225-2.


The interaction of the potent histamine H3-receptor ligands i.e. (R)alpha-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 guinea-pig hippocampus was not modified by thioperamide (up to 0.1 mM) and (R)alpha-methylhistamine stimulated cyclic AMP accumulation only at millimolar concentrations. Hence, both (R)alpha-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 alpha-fluoromethylhistidine in a synaptosomal fraction was not modified by mepyramine and zolantidine but was markedly enhanced by thioperamide at a low dose (ED50 = 2 mg/kg). Thioperamide also elicited a long-lasting decrease in synaptosomal histamine and increase in radioimmunoassayable N tau-methylhistamine. In contrast, (R)alpha-methylhistamine markedly 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 N tau-methylhistamine 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / physiology*
  • Brain Chemistry
  • Cyclic AMP / metabolism
  • Guinea Pigs
  • Histamine / metabolism
  • Histamine / physiology*
  • Histamine H1 Antagonists / pharmacology
  • Histamine H2 Antagonists / pharmacology
  • Histidine Decarboxylase / metabolism
  • In Vitro Techniques
  • Male
  • Methylhistamines / pharmacology
  • Neurons / physiology*
  • Piperidines / pharmacology
  • Pyrilamine / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, Histamine / drug effects*
  • Receptors, Histamine / physiology
  • Receptors, Histamine H3


  • Histamine H1 Antagonists
  • Histamine H2 Antagonists
  • Methylhistamines
  • Piperidines
  • Receptors, Histamine
  • Receptors, Histamine H3
  • Histamine
  • Cyclic AMP
  • Histidine Decarboxylase
  • Pyrilamine
  • thioperamide
  • N-methylhistamine