The proposed studies involve further investigations into the biochemical effects of amphetamine and ring-substituted derivatives, with particular emphasis on p-chloro-amphetamine (PCA) and fenfluramine. These drugs are of potential value as biochemical tools in clinical and preclinical studies and as therapeutic agents in the the treatment of depression and obesity. Therefore, it is critical that their biochemical effects in laboratory animals be understood. PCA causes an immediate, marked decrease in the levels of serotonin and tryptophan hydroxylase activity in the brains of rats, which lasts for several months after a single dose. A principal objective of the proposed research is an elucidation of the mechanism(s) of the initial, reversible and the long-term, toxic effects of PCA on serotonergic neurons in the brains of laboratory animals. Biochemical studies of the apparent differences in the action of PCA and fenfluramine are also planned. The long-term (toxic) biochemical effects of continuous exposure of rats and mice to amphetamine and related compounds will be investigated. In structure-activity studies, the potency and selectivity to induce toxic effects after continuous administration will be compared with in vitro potency as amine uptake inhibitors and as releasing agents. In-depth studies of amphetamine will examine several parameters of amine function and the role of active metabolites in the long-term effects produced by this CNS stimulant.