It has been proposed that, in a variety of tissues, guanosine 3':5'-monophosphate (cyclic GMP) is the intracellular mediator of muscarinic effects. This hypothesis was tested in the CA1 region of the hippocampus, in urethane-anaesthetized rats, by studying extracellularly muscarinic disinhibition of disfacilitation and the effect of dibutyryl cyclic GMP, muscarinic agents and an inhibitor of cyclic nucleotide-dependent kinase (H-8), all applied by microiontophoresis. The main findings were: (a) cyclic GMP analogues do not mimic disfacilitation or disinhibition produced by muscarinic agents; (b) N-(2-(methylamino)ethyl)-5-isoquinoline sulfonamide (H-8) does not prevent the excitatory actions of muscarinic agents; and (c) H-8 alone does not change the field responses. In conclusion, cyclic nucleotide-dependent kinases do not seem to play a major role in the on-going modulation of excitability in the hippocampus and cyclic GMP is unlikely to be a major intracellular messenger mediating directly or indirectly the excitatory actions of acetylcholine.