Serotonin and dopamine, both likely transmitter substances in Aplysia, stimulated formation of adenosine-3',5' monophosphate (cAMP) in ganglia, connectives, and identified nerve cell bodies. This widespread distribution suggests that receptors for the response are localized throughout the nervous system, as is adenyl cyclase. Both synthesis of cAMP-(3)H from precursor previously labeled in incubations with adenine-(3)H and total content of cAMP were stimulated up to 15-fold. The acetylcholine analogue carbachol, glutamate, norepinephrine, and histamine were inactive. Full stimulation occurred within 2-4 min of applying serotonin; the extent of the effect was half maximal at 6micro serotonin. Even in the continued presence of serotonin, the increased cAMP diminished with time. When serotonin was removed, tissue remained refractory for 15-20 min; sensitivity returned after 25 min. Serotonin stimulated cAMP after removal of extracellular Na, K, or Cl and in isotonic sucrose, with all extracellular ions removed. Elevating Mg, which blocked the stimulation of cAMP caused by synaptic activity, did not affect the response to serotonin. Thus the response appeared to be independent of transmitter release and of changes in synaptic potentials and current flow. The role of cAMP in neuronal functioning remains to be determined. Conditions which markedly increased cAMP in neurons, however, did not affect the rate of RNA synthesis, nor did they alter the distribution of phosphorylated adenine or uridine nucleotides.