Substituted amphetamines are known to selectively destroy serotonin (5-HT) nerve endings in distant projection fields of the dorsal raphe nuclei and the systemic administration of these drugs is widely used in investigations of the role of the central 5-HT system and of the mechanisms involved in their toxicity. Until now Sprague-Dawley rats were almost exclusively used for this purpose and the findings were thought to apply to other strains as well. We compared the long-term effects of the administration of different doses of para-chloroamphetamine (PCA) on three specific markers of the density of 5-HT presynapses, [3H]-paroxetine binding to 5-HT-transporters, tryptophan hydroxylase apoenzyme contents, and 5-HT levels in the frontal cortex of Sprague-Dawley and Wistar rats. PCA-treatment caused a dose dependent decline of all three parameters which was much more pronounced in Sprague-Dawley compared to Wistar rats. An i.p. dose of 4 mg PCA/kg body weight, which caused a severe, about 90% reduction of all three parameters of 5-HT innervation in Sprague-Dawley rats was almost ineffective in Wistar rats. The dose of 8 mg/kg which was required to eliminate about 80% of cortical 5-HT presynapses in Wistar rats was already lethal to Sprague-Dawley rats. The reasons of this different susceptibility of the 5-HT system in the two rat strains are unknown. Their elucidation will contribute to a better understanding of inherited differences in individual vulnerability to the neurotoxic effects of substituted amphetamines. The combined measurements of transporter density, of tryptophan hydroxylase apoenzyme contents, and of 5-HT levels is a powerful tool for the assessment of experimentally induced changes in the density of 5-HT innervation in distant projection fields of the raphe nuclei.