The proposed studies involve further investigations into the biochemical and behavioral effects of ring-substituted amphetamine derivatives, with particular emphasis on p-chloroamphetamine (PCA). PCA is of potential value both as a biochemical tool in clinical and preclinical studies, and as a therapeutic agent in the treatment of depression. Therefore, it is critical that its biochemical effects in laboratory animals be understood as completely as possible. Unlike amphetamine, PCA causes a marked reduction in the levels of 5- hydroxytryptamine and tryptophan hydroxylase activity in the brains of rats and mice. Moreover, following a single dose of PCA to rats, but not mice, these remain maximally reduced for two weeks with a slow recovery during the next few months. Since PCA disappears from rat brain with a half-life of 8.5 hours, it is important to look for an "active metabolite." A detailed examination of the biological disposition of PCA will include studies of the pattern of metabolites in rats and mice, the regional and subcellular distribution of the drug and its metabolites, and binding of the drug and/or metabolites to subcellular particles and macromolecules. C14-PCA will be used; separation and purification procedures will include systematic fractional extraction, paper and thin layer chromatography, and gas chromatography, with final identification of metabolites by gas chromatography-mass spectrometry. The duration of biochemical effects in other species, such as guinea pigs and rabbits will also be investigated. The motor effects of PCA are similar to those of amphetamine, except that tolerance to the former develops rapidly on repeated dosing. This may explain why PCA in man appears to be a true antidepressant rather than an amphetamine-like excitant. We will examine the neurochemical mechanisms which mediate this tolerance and the possibility of cross-tolerance with other CNS stimulants and/or hallucinogens.