CYCLIC ADENOSINE 3′,5′‐MONOPHOSPHATE FORMATION IN GUINEA‐PIG BRAIN SLICES: EFFECT OF H1‐ AND H2‐HISTAMINERGIC AGONISTS

Abstract

Abstract—A variety of histamine analogs elicit accumulations of radioactive cyclic AMP in guinea‐pig neocortical and hippocampal slices labelled during a prior incubation with [14C]adenine. The H1agonist, 2‐aminoethylthiazole, elicits accumulation of cyclic AMP in neocortical and hippocampal slices both in the absence or presence of adenosine. The presence of adenosine increases the maximum response to 2‐aminoethylthiazole and decreases the EC50 by nearly 10‐fold. In the absence of adenosine the effects of 2‐aminoethylthiazole are antagonized in hippocampal slices by both d‐brompheniramine and metiamide, while in the presence of adenosine only d‐brompheniramine is an effective antagonist. The H2‐agonist, 4‐methylhistamine, elicits a somewhat smaller accumulation of cyclic AMP than does 2‐aminoethylthiazole in both cortical and hippocampal slices. In the presence of adenosine the response to 4‐methylhistamine is enhanced, but is markedly lower than that seen with the combination of adenosine and 2‐aminoethylthiazole. The dose‐response relationship for 4‐methylhistamine in the presence of adenosine appears in hippocampal slices to consist of two components. The response to 4‐methylhistamine in the absence of adenosine is blocked by metiamide, while in the presence of adenosine the response is partially blocked by both H1 and H2‐antagonists. The accumulation of cyclic AMP elicited by histamine is greatly increased by adenosine but the EC50 is not significantly decreased. The results suggest that (i) both H1‐ and H2‐receptors regulate cyclic AMP‐formation in the central nervous system, (ii) the synergism between adenosine and histamine is mediated primarily by interaction with H1‐receptors and (iii) that adenosine greatly increases the affinity of the H1‐receptors for both H1 and H2‐agonists without affecting its affinity for histamine.