Pharmacological specificity of brain histamine H₂-receptors differs in intact cells and cell-free preparations

Abstract

Despite increasing evidence that histamine may be a neuro-transmitter in brain, the functions of putative histaminergic neurones are just beginning to be known^1,2. Both H₁- and H₂-receptors³ seem to be present in brain^4–7 and histaminergic neurones might control arousal mechanisms or carbohydrate metabolism, via H₁-receptors^8–11. The actions mediated by cerebral H₂-receptors are less clear mainly because available agonists and antagonists^3,12–15 do not cross the ‘blood–brain barrier’. However, on a histamine-sensitive adenylate cyclase from guinea pig brain homogenates with pharmacological properties similar to those of H₂-receptors^16,17 compounds like tricyclic antidepressants or promethazine were extremely potent antagonists^18,19 suggesting that this might represent the molecular basis of clinical antidepressant activity¹⁹. Although electrophysiological²⁰ and behavioural²¹ studies partially confirmed that one of these compounds, amitryptiline, could block cerebral histamine receptors in the living animal, their potency as H2-antihistamines has never been precisely established in intact brain cell preparations. Histamine strongly stimulates cyclic AMP synthesis in brain slices but, in contrast with homogenates, both H₁- and H₂-receptors are involved^4,5,22. As compounds like promethazine are potent H₁-antihistamines^7,8, we have developed a test specific for H₂-receptors consisting of the stimulation of cyclic AMP accumulation by impromidine, a potent and highly selective H₂-receptor agonist¹⁴, in slices from guinea pig hippocampus and using it find that H₂-receptors differ considerably in their drug discriminatory properties from those mediating the stimulation of adenylate cyclase activity in homogenates.