Cyclic nucleotides have been implicated in many long-lasting transmitter-induced effects on membrane conductance. One previously observed effect of cAMP on molluscan neurons is to induce a slow inward current, which has been further evaluated here in depolarized anterior and medial cells of the pleural ganglion of Aplysia californica in order to understand better its underlying ionic mechanisms and its sensitivity to a variety of pharmacological agents. This current, which appears to be the only cAMP-induced current seen in the anterior cells, was shown to invert at about +25 mV, that is, approximately 25-30 mV inferior to ENa. This reversal potential was lowered by about 15-16 mV when half of the extracellular Na was replaced by either mannitol or N- methyl-D-glucamine, whereas it was unaffected by changes in extracellular Cl, Ca, or Mg. The response persisted in seawater in which the Na had been totally replaced by K, and its reversal potential shifted towards more negative values. These data are consistent with the hypothesis that both Na and K ions permeate the channel, with a Na/K permeability ratio of approximately 2. Ca ions do not appear to permeate the channel, but they do have a marked inhibitory effect on the response amplitude, as do Mg ions when Ca is not present. Caffeine, intracellular acidification, and phosphodiesterase inhibitors enhance and prolong the response without changing its reversal potential. Previous studies have shown that both caffeine and intracellular acidification inhibit phosphodiesterase, and it is assumed that the common effect of these manipulations on the cAMP-induced inward current is mediated, at least partially, by the inhibition of that enzyme. In the medial cells of the pleural ganglion, this slow inward current is present, but is dominated in the depolarized cell by a cAMP-induced diminution in a Ca-activated K conductance (Kehoe, 1985b). This K conductance and, consequently, the noninverting, cAMP-induced inward current that reflects its diminution, were shown to disappear in Ca- free solutions, in the presence of isobutyl-1-methylxanthine (IBMX) or caffeine, and upon acidification of the cytoplasm. When this cAMP- sensitive K conductance is blocked, the presence of the inverting cAMP- induced cationic current is unmasked. The cAMP-induced cationic current is shown to have many properties in common with cyclic nucleotide- induced currents described in photoreceptors, olfactory receptor cilia, and cardiac myocytes, all of which have been shown to be outwardly rectifying cationic currents that are inhibited by divalent cations and do not involve the activation of a cAMP-dependent kinase.