Unitary extracellular recordings were made in in vitro rat brain slices to explore the effects of serotoninergic analogues on the spontaneous activity of substantia nigra reticulata (SNr) neurons. Most SNr neurons exhibited regular spontaneous firing (23.4 +/- 8.9 Hz, mean +/- S.E.M., n = 30) similar to that found in vivo. The most reproducible effect of serotonin (5-HT) was an increase in firing frequency found in 53% of the cells. The effect was concentration dependent and blocked by the 5-HT1/2 antagonist methysergide (1-10 microM) but unaffected by the 5-HT4- and 5-HT1-preferring antagonists DAU 6285 (5 microM) and metiothepin (5 microM), respectively. However, 5-HT also decreased the firing frequency in several neurons. In 19% of the neurons an inhibition was found alone but a biphasic response (inhibition and excitation) was found in another 28% of the neurons. Interestingly, the effect of the 5-HT-uptake inhibitor, duloxetine (100-400 nM), was frequency inhibition. Agonists that mimicked the 5-HT-induced inhibition were of the 5-HT1B-class (25 microM CP 93129 and 25 microM TFMPP). Neither the 5-HT2-antagonist ritanserin (5 microM) nor the GABA(A)-antagonist, bicuculline (30 microM) were able to block the inhibition suggesting that some SNr neurons may be directly inhibited by 5-HT.