Drug disposition as a factor in the lowering of brain serotonin by chloroamphetamines in the rat

Abstract

Brain serotonin content of rats treated 6 hr earlier was markedly reduced by 4-chloroamphetamine, slightly reduced by 3-chloroamphetamine, and not changed by 2-chloroamphetamine or amphetamine. In rats pretreated with desmethylimipramine (DMI), the reduction of serotonin caused by 4-chloroamphetamine was unchanged, but 3-chloroamphetamine was now equally as effective as 4-chloroamphetamine; amphetamine still had no effect, and 2-chloroamphetamine caused a slight elevation of serotonin. Levels of amphetamine, 2-chloroamphetamine and 3-chloroamphetamine were too low to detect in rat brain at 6 hr except in the rats pretreated with DMI to block para-hydroxylation. 4-Chloroamphetamine levels in brain were the same in controls and in DMI-pretreated rats. 4-Chloroamphetamine and 3-chloroamphetamine, which lowered serotonin equally in DMI-pretreated rats, were both present mainly in the particulate fraction after high speed centrifugation of brain homogenates, whereas 2-chloroamphetamine was evenly distributed between the supernatant and particulate fractions and amphetamine was present mainly in the supernatant fraction. The intrinsic ability of these compounds to lower serotonin is better demonstrated in DMI-pretreated rats in which metabolic differences between them are minimized; thus 3-chloro- and 4-chloroamphetamine are equally active. The association of those two drugs with brain particulate material is suggested to be related to their reduction of serotonin content.