Microglial and astroglial activation by 3,4‐methylenedioxymethamphetamine (MDMA) in mice depends on S(+) enantiomer and is associated with an increase in body temperature and motility

The S(+) enantiomer of MDMA, but not the R(−) enantiomer, activates microglia and astroglia in the mouse striatum, though less strongly than racemic MDMA. Combining both enantiomers produces no greater activation than S(+) alone. Only racemic MDMA slightly activates microglia in other brain regions. S(+) and racemic MDMA similarly increase motor activity and body temperature, while R(−) has no effect. Body temperature rise correlates with glial activation. The findings indicate additive rather than synergistic effects of the two enantiomers and highlight the need to study their separate contributions to MDMA's neuroinflammatory and neurotoxic effects.

Study at a glance

Abstract

Abstract Evidence is accumulating to suggest that 3,4‐methylenedioxymethamphetamine ( MDMA ) has neurotoxic and neuroinflammatory properties. MDMA is composed of two enantiomers with different biological activities. In this study, we evaluated the in vivo effects of S(+)‐ MDMA , R(−)‐ MDMA , and S(+)‐ MDMA in combination with R(−)‐ MDMA on microglial and astroglial activation compared with racemic MDMA , by assessment of complement type 3 receptor ( CD 11b) and glial fibrillary acidic protein ( GFAP ) immunoreactivity in the mouse striatum, nucleus accumbens, motor cortex, and substantia nigra. Motor activity and body temperature were also measured, to elucidate the physiological modifications paired with the observed glial changes. Similar to racemic MDMA (4 × 20 mg/kg), S(+)‐ MDMA (4 × 10 mg/kg) increased both CD 11b and GFAP in the striatum, although to a lower degree, whereas R(−)‐ MDMA (4 × 10 mg/kg) did not induce any significant glial activation. Combined administration of S(+) plus R(−)‐ MDMA did not induce any further activation compared with S(+)‐ MDMA . In all other areas, only racemic MDMA was able to slightly activate the microglia, but not the astroglia, whereas enantiomers had no effect, either alone or in combination. Racemic MDMA and S(+)‐ MDMA similarly increased motor activity and raised body temperature, whereas R(−)‐ MDMA affected neither body temperature nor motor activity. Interestingly, the increase in body temperature was correlated with glial activation. The results show that no synergism, but only additivity of effects, is caused by the combined administration of S(+)‐ and R(−)‐ MDMA , and underline the importance of investigating the biochemical and behavioral properties of the two MDMA enantiomers to understand their relative contribution to the neuroinflammatory and neurotoxic effects of MDMA .