L-5-Hydroxytryptophan (5-HTP) is a clinically useful antimyoclonic drug that is thought to act at serotonin (5-HT) receptors after decarboxylation to 5-HT. However, the chronic effects of 5-HTP on central 5-HT receptors and the activity of 5-HTP at 5-HT receptor subtypes have not been previously reported. In rats treated 28 but not 7 consecutive days with high doses of 5-HTP (50-200 mg/kg), cortical 5-HT2 (-20%) and 5-HT1 (-11%) sites were downregulated without altered receptor affinity, but only the changes in 5-HT2 sites were significant. In naive frontal cortex in vitro, however, 5-HTP and 5-HT were more active at 5-HT1 sites, and 5-HTP was inactive at 5-HT2 sites. The differential effects of high-dose 5-HTP on 5-HT receptors suggest that 5-HT2 receptor downregulation may be relevant either to the antimyoclonic effect of chronic 5-HTP therapy in posthypoxic myoclonus or to development of tolerance.