The effect of a single injection of d,1-p-chloro-N-methylamphetamine (PCMA) on 5-hydroxytryptamine (5-HT)- containing neurons in rat brain was investigated using fluorescence histochemical, electron microscopic and biochemical methods. PCMA caused in a dose-dependent manner (from 4.3 mg/kg), an increase of formaldehyde-induced indoleamine (IA) fluorescence in swollen non-terminal axons during the first 6 days and, in contrast, a diminution of IA fluorescence in nerve terminal regions for up to 42 days after treatment. These changes did not appear to be the result of destruction of 5-HT nerve terminals since at all time intervals investigated (12 h to 42 days), the fine structure and frequency of supra-ependymal 5-HT nerve terminals were unaffected. Moreover, no degenerating nerve terminals were observed in the suprachiasmatic nucleus. A marked transient decrease of IA fluorescence on day 2 in the 5-HT cell bodies B3-B9 was not followed by obvious morphological changes up to 42 days after PCMA. Therefore, the reduced 5-HT content of brain up to 42 days after treatment seems not to be due to a destruction of 5-HT neurons. Moreover, the damage to non-terminal 5-HT axons, as indicated by the 5-HT accumulation, seems not to be severe, at least not to those axons projecting to the cerebral ventricles and suprachiasmatic nucleus, since no degeneration of 5-HT nerve terminals was observed at any of the times investigated.