The psychotomimetic phencyclidine (PCP) alters various behavioural responses involving the serotonergic system including potentiating the discriminative stimulus effects of the phenethylamine hallucinogen, 2,5-dimethoxy-4-methylamphetamine (DOM). The present study was undertaken to test the hypothesis that PCP directly interacts with the 5-HT2A receptor. PC12 cells, a neuronal cell line, were stably transfected with the cDNA encoding the rat 5-HT2A receptor (PC12-5-HT2A). In these cells PCP and the related compounds, ketamine and dizocilpine, did not increase [3H]inositol phosphate generation nor did they alter 5-HT-stimulated phosphoinositide hydrolysis. These compounds also did not display appreciable affinity for the 5-HT2A receptor labelled with [3H]ketanserin. The present study indicates that the behavioural responses to PCP, ketamine and dizocilpine do not involve a direct interaction of these compounds with the 5-HT2A receptor.