Correlation between brain levels and biochemical effects of the optical isomers of p-chloroamphetamine.

The biochemical effects of d- and l-p-chloroamphetamine (PCA) were compared with the brain levels of the unchanged drug at various times after a single injection. Initially both isomers produced rapid and pronounced decreases in the whole brain levels of serotonin and 5-hydroxyindoleacetic acid, tryptophan hydroxylase activity and the synaptosomal uptake of 3-H-serotonin. At later times (e.g., 2 weeks), the effects of the d-isomer were much more pronounced than were those of the l-isomer. At intermediate times (2-4 days), a variable and dose-dependent recovery of synaptsomal uptake activity and tryptophan hydroxylase activity occurred after d-PCA. In both whole brain and forebrain, long-term reductions in these activities were found. However, in the midbrain, an area containing the cell bodies of serotonergic neurons, only a slight initial decrease in tryptophan hydroxylase activity occurred. The whole brain levels of the two isomers were equal from 4 to 96 hours after injection and declined exponentially in a single monophasic manner monophasic decine of the levels of PCA was found in forebrain and midbrain samples. Thus, the initial and long-term effects of PCA are apparently mediated by different mechanisms. The former is correlated with the brain levels of the unchanged drug; the latter is not. The lack of any indication of a biphasic decay curve after 10 half-lives and the intermediate recovery of serotonergic function do not support a reserpine-like mechanism for the long-term effects of PCA. Instead, a mechanism related to neurotoxicity is proposed.