Effects of lithium on central 5-HT function have been shown using electrophysiological, behavioural and neurochemical approaches. Chronic lithium administration, for example, enhances both electrophysiological and behavioural responses mediated by postsynaptic 5-HT1A receptors as well as increasing potassium-evoked and electrically evoked release of 5-HT from the hippocampus in in vitro slices and in vivo. Our studies have shown that potassium-channel blocking drugs increase 5-HT release in vivo, and others have shown that lithium suppresses potassium currents in some cell types. We therefore investigated in the rat the effect of short-term (3 days) and long-term (21 days) lithium on 5-HT release evoked by potassium-channel blockade, using in vivo microdialysis. Long-term lithium treatment enhanced 5-HT efflux in rat hippocampus produced by 4-aminopyridine (4-AP) perfused in microdialysis fluid by as much as 100% within 40 min, compared with non-lithium-treated control rats. Short-term lithium treatment did not enhance 4-AP-induced 5-HT efflux. The effect of local tetraethylammonium chloride (TEA) on hippocampal 5-HT release was unaltered by long-term lithium treatment. In addition, neither the effect of local perfusion with 4-AP on efflux of striatal 5-HT, or dopamine in nucleus accumbens, was altered by chronic lithium treatment. These results show that long-term lithium treatment enhances 4-AP-stimulated efflux of 5-HT in the hippocampus, but not in the striatum, nor dopamine output in the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)