P-Chloramphetamine: Selective neurotoxic action in brain.

Injection of 2.5,5, 10, or 20 milligrams of p-chloroamphetamine per kilogram of body weight into rats produced evidence of cytopathological changes in sections of brain stained by a Nissl or silver method. As early as 1 day after drug injection cells demonstrated an intense Nissl staining, intense argyrophilia, cellular shrinkage, and perineuronal spaces. At 30 days after injection both stains revealed cellular debris and glial reactions characteristic of cellular dissolution. The neurotoxic effects of 2.5, 5, or 10 milligrams of p-chloroamphetamine per kilogram were primarily restricted to an area of the ventral midbrain tegmentum corresponding to the distribution of the B-9 serotonergic cell group. After 20 milligrams of p-chloroamphetamine per kilogram there was also evidence of neurotoxic effects on cells within the substantia nigra. These results confirm previous suggestions that the long-term reduction in serotonin content of brain, tryptophan-5-hydroxylase activity, and uptake of serotonin after injection of p-chloroamphetamine is due to a neurotoxic effect of the drug or some metabolite on serotonergic cell bodies.