Extracellular recording techniques were used to study the effects of the nitric oxide releasing agents diethylamine-NO (DEA-NO) and S-nitroso-N-acetyl-penicillamine (SNAP) on synaptic transmission in the intermediate and medial part of the hyperstriatum ventrale (IMHV), a part of the domestic chick forebrain that is essential for some forms of early learning. The field response evoked by local electrical stimulation was recorded in the IMHV in an in vitro slice preparation. DEA-NO (100-200 mgr) significantly depressed the field response in a concentration dependent and reversible manner. However, the depression produced by perfusion with 400 mgr DEA-NO, was not reversed following washout of the drug. With 400 mgr DEA-NO, NO reaches a maximum concentration of 10 mgr at 2 min of perfusion, and then declines slowly. SNAP (400 mgr) produced an effect similar to 400 mgr DEA-NO. Neither the immediate nor the longer-term depressive effect of NO is mediated by activation of guanylyl cyclase because in the presence of both low and high doses of ODQ, a potent and selective inhibitor of NO-stimulated guanylyl cyclase, NO produced the same depression of the field response. There is evidence however that the IMHV possesses c-GMP responsive elements since direct perfusion of 8-Br-cGMP (1 mM) produced a long-term but not an immediate depression. The long-term depression produced by 400 mgr DEA-NO was eliminated in the presence of either a selective adenosine A(1) receptor antagonist or an ADP-ribosyltransferase inhibitor. It was also possible to prevent the long-term effect in the presence of tetraethyl ammonium a K(+)-channel blocker. These results suggest that the NO may be acting presynaptically in a synergistic fashion with the adenosine A(1) receptor to depress transmitter release.