We have examined the interactions, in eliciting cAMP accumulation, between vasoactive intestinal polypeptide (VIP) and the three monoamines norepinephrine (NE), histamine (HIS), and serotonin (5-hydroxytryptamine, 5-HT) in mouse cerebral cortical slices. We have observed that NE and HIS, but not 5-HT, act synergistically with VIP to increase cAMP levels. The rank-order of potency of several adrenergic agonists in potentiating the effect of VIP on cAMP levels is the following: epinephrine greater than NE greater than phenylephrine much greater than clonidine, with EC50 of 2.2, 5, and 10 microM, respectively (clonidine being only marginally effective). This pharmacological profile is characteristic of the activation of alpha 1-adrenergic receptors. This contention is substantiated by the observation that the potentiating effect of NE is antagonized by the selective alpha 1-adrenergic antagonist prazosin at nanomolar concentrations. The potentiating effect of HIS is mediated by H1-histaminergic receptors since it is antagonized by the selective H1-receptor antagonist mepyramine but not by cimetidine, a selective H2-receptor antagonist. The synergistic interaction between VIP and NE is also observed in the presence of the adenosine antagonist theophylline, thus discarding the possibility of a mediation of the synergism by adenosine released by VIP.(ABSTRACT TRUNCATED AT 250 WORDS)