BACKGROUND The 5-hydroxytryptamine (5-HT)(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) alters temporal differentiation of behaviour on the free-operant psychophysical procedure, displacing the psychophysical curve to the left, thereby reducing the indifference point T(50). However, it is not known whether this effect of 8-OH-DPAT is mediated by an action of the drug at somatodendritic autoreceptors or at postsynaptic receptors. OBJECTIVE To compare the effects of 8-OH-DPAT on performance on the free-operant psychophysical procedure in normal (sham-lesioned) rats and in rats whose 5-HTergic pathways had been lesioned by means of intra-raphe injections of the selective neurotoxin 5,7-dihydroxytryptamine (5,7-DHT). METHODS Twelve rats received 5,7-DHT-induced lesions of the median and dorsal raphe nuclei, and twelve received sham lesions. They were trained under the free-operant psychophysical procedure to press two levers (A and B) in 50-s trials, during which reinforcement was provided intermittently for responding on A in the first half and B in the second half of the trial. Percentage responding on B (%B) was recorded in successive 5-s epochs of the trials; logistic psychophysical curves were fitted to the data from each rat for the derivation of timing indices [T(50) (time corresponding to %B=50%) and Weber fraction] following treatment with acute doses of 8-OH-DPAT (25, 50, 100, 200 microg kg(-1), s.c.) and saline (vehicle-alone treatment). Levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), noradrenaline and dopamine were measured in forebrain regions after the completion of the experiment. RESULTS Under the vehicle-alone condition, the lesioned group displayed a greater propensity for switching between the levers, but T(50) and the Weber fraction did not differ between the groups. In both groups, 8-OH-DPAT shifted the psychophysical curve to the left, significantly reducing T(50) at the 200-microg kg(-1) dose; the effect of 8-OH-DPAT did not differ significantly between the groups. Levels of 5-HT and 5-HIAA in the lesioned group were about 10% of those in the sham-lesioned group; there was no effect of the lesion on catecholamine levels. CONCLUSIONS The results confirm that 8-OH-DPAT disrupts temporal differentiation in the free-operant psychophysical schedule, reducing the indifference time, T(50). The failure of central 5-HT depletion to alter the effect of 8-OH-DPAT suggests that this effect may be mediated by stimulation of postsynaptic 5-HT(1A) (or possibly 5-HT(7)) receptors rather than somatodendritic 5-HT(1A) autoreceptors.