Comparison of the effects of 6-chloro-2-aminotetralin and of Org 6582, a related chloroamphetamine analog, on brain serotonin metabolism in rats

Abstract

Org 6582 and 6-chloro-2-aminotetralin can be viewed as p-chloroamphetamine analogs having rigid conformation. Because p-chloroamphetamine exerts multiple actions on brain serotonin neurons, we compared the effect of these rigid analogs on certain parameters of brain serotonin metabolism in rats to determine the extent of dissociation of these multiple actions. 6-Chloro-2-aminotetralin resembled p-chloroamphetamine in lowering brain levels of tryptophan hydroxylase, serotonin and 5-hydroxyindoleacetic acid (5-HIAA) in rat brain, though its effects were less than those of p-chloroam-phetamine and were short-lasting in contrast to the permanent neurotoxic effects of p-chloroamphetamine. Org 6582 did not lower tryptophan hydroxylase or serotonin levels in rat brain; its lowering of 5-HIAA levels can be attributed to its inhibition of serotonin re-uptake. In vitro, Org 6582 was a slightly stronger inhibitor of serotonin uptake than was 6-chloro-2-aminotetralin but a distinctly weaker inhibitor of monoamine oxidase. Inhibition of uptake into serotonin neurons in vivo was evaluated by measuring the ability of 6-chloro-2-aminotetralin and of Org 6582 to antagonize the neurotoxic effects (lowering of serotonin levels or lowering of serotonin uptake) produced by p-chloroamphetamine. In these experiments, Org 6582 but not 6-chloro-2-aminotetralin was a potent inhibitor of uptake into serotonin neurons in vivo, in agreement with the findings of Goodlet et al. [I. Goodlet, S. E. Mireylees and M. F. Sugrue, Br.J. Pharmac. 56, 367P (1976)] and of Sugrue et al. [M. F. Sugrue, I. Goodlet and S. E. Mireylees, Eur.J. Pharmac. 40, 121 (1976)] on Org 6582.