Lesions of the ascending serotonergic pathways and antinociceptive effects after systemic administration of p-chloroamphetamine in mice

The present study reports a method for lesioning of the ascending serotonergic system. The neurotoxic substance p-chloroamphetamine (PCA) was given IP on 2 consecutive days (40 mg/kg/day). After each injection, the animals were kept at 4°C for 4 hr since a lower dose of PCA (25 mg/kg) induced severe hyperthermia. The mortality rate was 12%, considerably lower than previously reported in similar studies. Evaluated 9 days after the last injection of PCA, the uptake of 14C-5-HT into cortical and hippocampal crude synaptosomal preparations was reduced by 50 and 60%, respectively, while the uptake into spinal synaptosomes was unaffected. The uptake of 3H-NA was not significantly altered in any of the structures. Measurements of PCA performed 30 min to 4 hr after IP injections of 5 to 40 mg/kg demonstrated higher concentrations in the cortex than in the lumbar spinal cord. Administration of PCA (5 mg/kg) had an acute antinociceptive effect in the hot-plate and formalin tests, but not in the tail-flick test. Prior treatment with neurotoxic doses of PCA prevented the antinociception but had in itself no effect on the responsiveness in any of the tests. Thus systemic administration of PCA produces highly selective and functional lesions of the ascending serotonergic pathways in mice.