The effects of four tricyclic antidepressants, nortriptyline, iprindole, chlorimipramine and desipramine on adenosine-evoked depressions of the firings of rat cerebral cortical neurones has been studied. When applied iontophoretically, all four substances enhanced the depressant actions of iontophoretically applied adenosine but did not affect the depressant actions of the uptake-resistant analogue, adenosine 5'-N-ethylcarboxamide (NECA). Nortriptyline and iprindole administered intravenously (1 mg kg-1) enhanced the depressant actions of iontophoretically applied adenosine. When applied by larger iontophoretic currents, all four antidepressants inhibited the firing of cerebral cortical neurones. Chlorimipramine- and desimipramine-elicited depressions were antagonized by intravenously administered caffeine, an adenosine antagonist. Earlier studies showed the tricyclic antidepressants inhibit the uptake of adenosine by rat brain cerebral cortical synaptosomes. The present results demonstrate that four antidepressants are able to potentiate the action of adenosine and that this occurs when these compounds are given in behaviourally meaningful doses. The specificity of the potentiation is demonstrated by the failure of these compounds to potentiate the depressant actions of an uptake-resistant analogue of adenosine, NECA. Antagonism of the inhibitory effects of the antidepressants on neuronal firings by caffeine, indicates that these compounds can enhance the extracellular levels of endogenously released adenosine sufficiently to depress cell firing.