Regional variation in the characteristics of histamine H1-agonist mediated breakdown of inositol phospholipids in guinea-pig brain

Abstract

The position of dose-response curves for histamine-induced accumulation of [3H]-inositol 1-phosphate ([3H]-IP1) in lithium-treated slices of guinea-pig brain prelabelled with [3H]-inositol differed significantly between cerebellum (EC50 5.1 +/- 1.0 microM) and cerebral cortex (EC50 16.3 +/- 0.7 microM). The Hill coefficients of the curves, 1.33 +/- 0.28 and 1.24 +/- 0.03, respectively, did not differ significantly. 2-Methylhistamine, N alpha,N alpha-dimethylhistamine and betahistine were partial agonists in both cerebellum and cerebral cortex, but all produced a greater percentage of the maximum response to histamine in cerebellar slices. In hippocampal slices the response of the partial agonists was intermediate between that in cerebellum and that in cerebral cortex. The four agonists produced an appreciable accumulation of [3H]-inositol 1-phosphate in cerebellar slices even in the absence of Li+ ion. The EC50 and Hill coefficients characterizing the dose-response curves for the four agonists were the same whether 10 mM LiCl was present or not. The affinity constant for mepyramine inhibition of the histamine-induced response was similar in cerebellum, 4.2 +/- 0.6 X 10(8) M-1, and cerebral cortex, 4.6 +/- 1.0 X 10(8) M-1. Curves of mepyramine inhibition of the responses to a fixed concentration of histamine gave no indication of any second component in the response to histamine in either cerebellum or cerebral cortex. The parameters of histamine inhibition of [3H]-mepyramine binding were similar in homogenates of guinea-pig cerebellum and cerebral cortex. These results indicate that H1-agonist-induced accumulation of IP1 may not be as directly related to agonist-receptor interaction as simple reaction schemes suggest.