HIPPOCAMPAL SOMATOSTATIN RECEPTORS AND MODULATION OF ADENYLYL-CYCLASEACTIVITY IN HISTAMINE-TREATED RATS

In the present study, the effects of an intracerebroventricular (i.c.v .) dose of histamine (0.1, 1.0 or 10.0 mu g) on the hippocampal somato statin (SS) receptor/effector system in Wistar rats were investigated. In view of the rapid onset of histamine action, the effects of histam ine on the somatostatinergic system were studied 2 h after its adminis tration. Hippocampal SS-like immunoreactivity (SSLI) levels were not m odified by any of the histamine doses studied. SS-mediated inhibition of basal and forskolin (FK)-stimulated adenylyl cyclase (AC) activity was markedly increased in hippocampal membranes from rats treated with 10 mu g of histamine (23% +/- 1% vs. 17% +/- 1% and 37% +/- 2% vs. 23 % +/- 1%, respectively). In contrast, neither the basal nor the FK-sti mulated enzyme activities were affected by histamine administration. T he functional activity of the hippocampal guanine-nucleotide binding i nhibitory protein (G(i) protein), as assessed by the capacity of the s table GTP analogue 5'-guanylylimidodiphosphate (Gpp[NH]p) to inhibit F K-stimulated AC activity, was not modified by histamine administration . These data suggest that the increased response of the enzyme to SS w as not related to an increased functional activity of G(i) proteins. I n fact, the increased AC response to SS in hippocampal membranes from histamine (10 mu g)-treated rats was associated with quantitative chan ges in the SS receptors. Equilibrium binding data obtained with [I-125 ]Tyr(11)-SS indicate an increase in the number of specific SS receptor s (541 +/- 24 vs. 365 +/- 16 fmol/mg protein, P < 0.001) together with a decrease in their apparent affinity (0.57 +/- 0.04 vs. 0.41 +/- 0.0 3 nM, P < 0.05) in rat hippocampal membranes from histamine (10 mu g)- treated rats as compared to control animals. With the aim of determini ng if these changes were related to histamine binding to its specific receptor sites, the histaminergic H-1 and H-2 receptor antagonists mep yramine and cimetidine, respectively, were administered 1 h before his tamine injection. The pretreatment with mepyramine or cimetidine induc ed an increase in the number and affinity constant of the SS receptors whereas the simultaneous pretreatment with both histamine antagonists prevented the histamine-induced changes in SS binding to its receptor s. Since the hippocampal SS receptor/effector system is modulated by h istamine, it is tempting to speculate that in the hippocampus, SS coul d be involved as a mediator of the histamine effects on behaviors such as learning and memory.