p-methylthioamphetamine is a potent new non-neurotoxic serotonin-releasing agent.

Summary

p-Methylthioamphetamine (MTA) is a potent and selective serotonin releaser that appears to lack the serotonin neurotoxic effects seen with p-chloroamphetamine (PCA). MTA was about twice as potent as PCA at inhibiting serotonin uptake, but 7 to 10 times less potent at inhibiting dopamine and norepinephrine uptake. In drug discrimination tests, MTA was nearly as effective as PCA in animals trained to recognize MDMA or related compounds. MTA also caused dose-dependent serotonin release from rat brain slices similar to PCA. However, a high dose of PCA reduced serotonin and its metabolite by 70-90% in brain regions, while twice the molar dose of MTA had no such effect, suggesting MTA is not neurotoxic to serotonin neurons.

Study at a glance

Abstract

p-Methylthioamphetamine (MTA), was compared to p-chloroamphetamine (PCA) in a number of pharmacological assays. MTA was about 2-fold more potent than PCA at inhibiting synaptosomal uptake of [3H]5-hydroxytryptamine ([3H]5-HT), and about 7-fold and 10-fold less potent than PCA at inhibiting synaptosomal uptake of [3H]dopamine and [3H]norepinephrine, respectively. In drug discrimination assays, MTA was nearly equipotent to PCA in animals trained to discriminate saline from 3,4-methylenedioxymethamphetamine (MDMA), or two related analogues S-(+)-N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (S-MBDB) or 5-methoxy-6-methyl-2-aminoindan (MMAI). MTA caused dose-dependent increases of tritium efflux from superfused rat frontal cortex slices preloaded with [3H]5-HT, comparable to that induced by an equal molar concentration of PCA. The potential neurotoxicity of MTA was examined by measuring monoamine and metabolite levels at one week following an acute dose. A 10 mg/kg dose of PCA caused a 70-90% decrease of cortical, hippocampal and striatal 5-HT and 5-hydoxyindoleacetic acid (5-HIAA) levels, while twice the molar dose of MTA (21.3 mg/kg) had no effect. Thus, MTA is a potent, selective, serotonin releaser, apparently devoid of serotonin neurotoxic effects. This work also supports the idea that catecholamine systems may play a critical role in the neurotoxicity of PCA-like compounds.