Autoregulation of histamine release in brain by presynaptic H 3-receptors

Abstract

Regulation of histamine release was studied mainly on brain slices prelabeled with l-[ 3-H]histidine and depolarized by increased extracellular K + concentration or veratridine in a non-superfused system. The released 3H-labeled amines, isolated by ion-exchange chromatography from a large excess of 3H-labeled precursor consisted by more than 95% of unchanged [ 3H]histamine. Exogenous histamine reduced the release of neosynthesized [ 3H]histamine via stimulation of previously characterized H 3-receptors whereas it did not modify the 3H-labeled amine release from slices prelabeled with preformed [ 3H]histamine. The maximal inhibitory effect of exogenous histamine progressively diminished as the strength of the depolarizing stimulus or the external Ca 2+ concentration were elevated. On the contrary H 3-receptor antagonists like impromidine or burimamide enhanced the depolarization-induced release of [ 3H]histamine, an effect which was particularly marked when slices were loaded with histamine by preincubation with [ 3H]histidine in high concentration. These results suggest that the inhibition of [ 3H]histamine release by exogenous histamine acting via H 3-receptor stimulation is mediated by a restricted access of Ca 2+ and that its extent is influenced by the degree of autostimulation by endogenous histamine as well as, possibly, by actual internal Ca 2+ concentration. In addition the decrease in external Ca 2+ concentration shifted rightwards the concentration-response curve to histamine. The autoinhibitory effect of exogenous histamine was found on slices from various regions, known from lesion studies to contain terminals of extrinsic histaminergic neurons. It did not apparently involve interneurones, not being prevented in slices in which the traffic of action potentials was blocked by tetrodotoxin. It also remained unaffected in striatal slices in which the neuronal cell-bodies were selectively destroyed by prior local infusion of kainic acid. Finally exogenous histamine inhibited [ 3H]histamine release from depolarized synaptosomes of rat cerebral cortex, with anEC 50 value similar to that found with slices and was antagonised by impromidine with an apparentK i value similar to that displayed at H 3-receptors. It is concluded that histamine modulates its own release from cerebral neurones by interacting with H 3-presynaptic autoreceptors and via mechanisms similar to those previously evidenced on other aminergic systems.