Slow synaptic excitation and inhibition were studied with intracellular microelectrodes in submucous ganglion cells of the guinea pig ileum. Elevation of adenosine 3',5'-cyclic monophosphate (cAMP) after application of forskolin or the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) resulted in slowly activating depolarization of the membrane potential. The depolarization was associated with increased input resistance, enhanced excitability, and suppression of hyperpolarizing afterpotentials. This occurred in AH/type 2 but not S/type 1 neurons. The action of forskolin or IBMX mimicked slow synaptic excitation in the same neurons. Focal electrical stimulation also evoked slow inhibitory postsynaptic potentials (IPSPs). The amplitude and duration of the IPSPs were increased by forskolin or a membrane-permeant analogue of cAMP. Treatment with phentolamine, yohimbine or idazoxan suppressed the IPSPs before and after potentiation by forskolin, suggesting that the IPSPs were mediated by release of norepinephrine acting at alpha 2-adrenoceptors. Application of adenosine or selective adenosinergic A1 agonists suppressed or abolished the IPSPs. The results suggest that elevation of cAMP facilitates the release of norepinephrine at alpha 2-synapses on submucous neurons of guinea pig small bowel.