RAT STRAIN DIFFERENCES IN THE VULNERABILITY OF SEROTONERGIC NERVE-ENDINGS TO NEUROTOXIC DAMAGE BY P-CHLOROAMPHETAMINE

Substituted amphetamines are known to selectively destroy serotonin (5 -HT) nerve endings in distant projection fields of the dorsal raphe nu clei and the systemic administration of these drugs is widely used in investigations of the role of the central 5-HT system and of the mecha nisms involved in their toxicity. Until now Sprague-Dawley rats were a lmost exclusively used for this purpose and the findings were thought to apply to other strains as well. We compared the long-term effects o f the administration of different doses of para-chloroamphetamine (PCA ) on three specific markers of the density of 5-HT presynapses, [H-3]- paroxetine binding to 5-HT-transporters, tryptophan hydroxylase apoenz yme 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 comp ared to Wistar rats. An i.p. dose of 4 mg PCA/kg body weight, which ca used a severe, about 90% reduction of all three parameters of 5-HT inn ervation in Sprague-Dawley rats was almost ineffective in Wistar rats. The dose of 8 mg/kg which was required to eliminate about 80% of cort ical 5-HT presynapses in Wistar rats was already lethal to Sprague-Daw ley rats. The reasons of this different susceptibility of the 5-HT sys tem in the two rat strains are unknown. Their elucidation will contrib ute to a better understanding of inherited differences in individual v ulnerability to the neurotoxic effects of substituted amphetamines. Th e combined measurements of transporter density, of tryptophan hydroxyl ase apoenzyme contents, and of 5-HT levels is a powerful tool for the assessment of experimentally induced changes in the density of 5-HT in nervation in distant projection fields of the raphe nuclei.