The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine

Substituted amphetamines MDMA, methamphetamine, PCA, and fenfluramine all release serotonin from nerve endings through a shared mechanism. PCA and fenfluramine are the most potent, MDMA is less potent, and methamphetamine is much less potent. Combining two drugs at half-effective concentrations does not increase release beyond either drug alone. The serotonin reuptake blockers fluoxetine and cocaine inhibit release from all four drugs equally. However, at low concentrations that block reuptake, these amphetamines do not reduce release caused by higher concentrations, indicating their uptake blockade differs from that of fluoxetine or cocaine.

Study at a glance

Abstract

The abilities of the substituted amphetamines 3,4-methylenedioxymethamphetamine (MDMA), methamphetamine, p-chloroamphetamine (PCA) and fenfluramine to induce synaptosomal [3H]serotonin (5-HT) release were compared using a novel microassay system. The rank order of release potencies was found to be (+/-)PCA congruent to (+)-fenfluramine greater than (+)-MDMA much greater than (+)-methamphetamine. Combination of two drugs at their EC50 did not cause more release than either drug alone at an equivalent concentration. In addition, the 5-HT uptake blockers fluoxetine and cocaine inhibited the release induced by MDMA, methamphetamine, PCA and fenfluramine to the same percentage. However, threshold concentrations of the substituted amphetamines known to inhibit uptake did not attenuate the release caused by higher concentrations of these compounds. These results suggests that MDMA, methamphetamine, PCA and fenfluramine cause 5-HT release via a common mechanism. Furthermore, these results indicate that the 5-HT uptake blockade induced by these substituted amphetamines in vitro is different from that induced by either fluoxetine or cocaine.