Head-twitch response and phosphatidylinositol (PIP) hydrolysis in cortex and spinal cord were measured after single or chronic (21 days) administration of paroxetine to normal mice or to mice neonatally treated with 5,7-dihydroxytryptamine, a serotonergic neurotoxin. In normal animals, a down-regulation of 5-HT-receptor numbers after chronic paroxetine was suggested by the attenuation of head-twitch responses compared with a single dose. There was a concomitant decrease in PIP hydrolysis. In DHT-treated animals, although changes in behavioural responses were comparable to those in normals, PIP hydrolysis in cortex and spinal cord after chronic paroxetine increased significantly. These results demonstrate that head-twitch responses and PIP hydrolysis may not be mediated by the same receptor and that the effects of chronic administration of paroxetine depend on the functional state of the serotonergic pathways.