Incubation (45 min) of slices of guinea-pig cerebral cortex with adenosine alone had no significant effect on the accumulation of [3H]-inositol phosphates but enhanced the response to histamine H1-receptor stimulation in a concentration-dependent manner. The effect of adenosine on agonist-stimulated inositol phospholipid hydrolysis appeared to be selective for histamine H1-receptor stimulation since it did not augment the phosphoinositide responses to carbachol, noradrenaline, 5-hydroxytryptamine or elevated KCl. The accumulation of [3H]-inositol phosphates induced by histamine increased linearly between 5 and 45 min incubation with agonist. However, following the simultaneous addition of histamine and adenosine, there was a marked delay in the appearance of the augmentation produced by adenosine. The augmentation of [3H]-inositol phosphate accumulation was mimicked by a number of adenosine analogues. The rank order of potency was; cyclopentyladenosine greater than R-phenyl-isopropyladenosine 5'-N-ethylcarboxamidoadenosine greater than 2-chloroadenosine. This is consistent with the order expected for an adenosine A1-receptor effect but the EC50 values were in the micro- rather than nanomolar range. The response to 2-chloroadenosine was antagonized by the xanthine adenosine-antagonists, cyclopropyltheophylline, 8-phenyltheophylline, 3-isobutyl-1-methylxanthine and theophylline, and the non-xanthine alloxazine.