Effects of histamine H3-receptor ligands on various biochemical indices of histaminergic neuron activity in rat brain.
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.
Garbarg
M
M
Unité de Neurobiologie et Pharmacologie, INSERM, Centre Paul Broca, Paris, France.
Tuong
M D
MD
Gros
C
C
Schwartz
J C
JC
D000818:Animals; D001921:Brain / Q000502:physiology*; D001923:Brain Chemistry; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000378:metabolism / Q000502:physiology*; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011738:Pyrilamine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011968:Receptors, Histamine / Q000187:drug effects* / Q000502:physiology; D018100:Receptors, Histamine H3
D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D008761:Methylhistamines; D010880:Piperidines; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D006632:Histamine; D000242:Cyclic AMP; D006640:Histidine Decarboxylase; D011738:Pyrilamine; C052075:thioperamide; C048140:N-methylhistamine