Desensitization of histamine H1 receptor-mediated inositol phosphate accumulation in guinea pig cerebral cortex...

1. Histamine stimulated the production of [3H]-inositol phosphates in untreated (control) guinea-pig cerebral cortex slices with a best-fit EC50 of 17 +/- 4 microM, and a best-fit maximum response of 385 +/- 23% over basal accumulation. 2. Histamine pretreatment desensitized guinea-pig cortex slices to a subsequent challenge with histamine, which was observed as a reduction in the best-fit maximum response to 182 +/- 32% over basal accumulation. 3. The time-course for the histamine-induced production of [3H]-inositol phosphates was approximately linear over 90 min of stimulation in both control and histamine pretreated slices. The rate of production in pretreated slices was significantly slowed compared to control, such that by 90 min of histamine stimulation the desensitized slices produced 2.8 times the basal [3H]-inositol phosphate accumulation compared to 5.3 fold the basal [3H]-inositol phosphate accumulation in the control slices. 4. Displacement of [3H]-mepyramine binding to homogenates of guinea-pig cerebral cortex by mepyramine and histamine revealed that histamine pretreatment did not alter the apparent affinity of the H1 receptor for histamine (control Kd = 6.3 +/- 0.7 microM, desensitized Kd = 7.9 +/- 1.6 microM) or mepyramine (control Kd = 3.4 +/- 0.8 nM, desensitized Kd = 3.4 +/- 1.3 nM), nor was there any reduction in the calculated maximum number of [3H]-mepyramine binding sites (control Bmax = 192 +/- 31 fmol mg-1 protein, desensitized Bmax = 220 +/- 50 fmol mg-1 protein). 5. The histamine-mediated desensitization of response in guinea-pig slices was mediated by the HI receptor subtype, since the attentuated maximum histamine-stimulated [3H]-inositol phosphate accumulation could not be prevented by inclusion of an H2- (ranitidine) and an H3- (thioperamide) receptor antagonist during the pretreatment period.6. The desensitized histamine-stimulated [3H]-inositol phosphate accumulation recovered to 90% of control levels over a period of 150 min after the removal of the conditioning dose of histamine, with a half-time of recovery of about 95 min.