The combined effects of 3,4-methylenedioxymethamphetamine (MDMA) and selected substituted methcathinones on measures of neurotoxicity

Summary

Mice given MDMA alone at a high dose showed temporary decreases in dopamine and tyrosine hydroxylase in the striatum and an increase in a marker of astrocyte activation (GFAP). When the methcathinones methylone or MDPV were combined with a lower MDMA dose, they did not affect dopamine or tyrosine hydroxylase levels but blocked the MDMA-induced increase in GFAP. Seven days after treatment, all measures returned to normal, indicating the changes were transient. Most drug groups caused an initial drop in body temperature followed by a gradual rise, but MDPV did not produce this pattern, suggesting it affects thermoregulation differently.

Study at a glance

Abstract

The rise in popularity of substituted methcathinones (aka “bath salts”) has increased the focus on their neurotoxic effects. Two commonly abused methcathinones, 3,4-methylenedioxymethcathinone (methylone, MDMC) and 3,4-methylenedioxypyrovalerone (MDPV), are often concomitantly ingested with the illicit drug 3,4-methylenedioxymethamphetamine (MDMA). To examine potential neurotoxic effects of these drug combinations, C57BL/6J mice were administered 4 i.p. injection of the drugs, at 2 h intervals, either singularly: MDMA 15 or 30 mg/kg, methylone 20 mg/kg, MDPV 1 mg/kg; or in combination: methylone/MDMA 20/15 mg/kg, MDPV/MDMA 1/15 mg/kg. Drug effects on thermoregulation were characterized and striatal tissue analyzed after 2 or 7 days for dopamine (DA) and tyrosine hydroxylase (TH) levels, as well as glial fibrillary acidic protein (GFAP) expression. Two days following drug administration, DA and TH were decreased only in the MDMA 30 mg/kg group, whereas GFAP expression was dose-dependently increased by MDMA alone. While the combination of the methcathinones with the lower MDMA dose did not affect DA or TH levels, both blocked the MDMA-induced increase in GFAP expression. Seven days following drug administration, there were no significant differences in DA, TH, or GFAP for any treatment group, indicating that changes in DA, TH, and GFAP were transient. Five of the six drug groups exhibited acute hypothermia followed by gradually increasing temperatures. Animals treated with MDPV did not exhibit these biphasic temperature changes, and resembled the saline group. These results indicate that specific effects of both methylone and MDPV on DA depletion or astrocyte activation in the striatum are not additive with effects of MDMA, but block astrogliosis caused by MDMA alone. Additionally, MDPV modulates thermoregulation through a different mechanism than methylone or MDMA.