A repeated low-dose regimen of MDMA has transient next-day effects on locomotor activity, anxiety-like behavior, and brain serotonin levels, with no effect on anhedonia-like behavior, in both female and male rats

Repeated low doses of MDMA (2.5 mg/kg) caused mild anxiety-like behavior in rats one day after exposure, but this effect was confounded by reduced movement and did not persist at 15 days. Higher doses (5 mg/kg) did not produce anxiety-like behavior. Sucrose preference, a measure of anhedonia, increased over time and was unaffected by MDMA or sex. Brain analysis showed reduced serotonin levels in the nucleus accumbens one day after both MDMA doses, but not in the prefrontal cortex or dorsal hippocampus. These transient effects suggest that low-dose MDMA used clinically may be tolerated without limiting therapeutic benefit.

Study at a glance

Abstract

MDMA (3–4 methylenedioxymethamphetamine) assisted psychotherapy has gained considerable attention as a potential adjuvant therapy for post-traumatic stress disorder (PTSD). Reports of the nonmedical use of MDMA suggest its adverse effects may include anxiety and anhedonia. However, the time course of these signs and symptoms and the potential alterations in neurotransmitter levels that may underlie these conditions are not well understood. We subjected cohorts of male and female Sprague Dawley rats to MDMA (2.5 or 5 mg/kg) or saline (1 ml/kg), with each dose given three times at two-hour intervals. Anxiety-like behavior (open field test [OFT]/elevated plus maze [EPM]/light dark box [LDB] assays) was measured 1 and 15 days after MDMA. Anhedonia-related behavior (sucrose preference test [SPT]) was also measured for five successive days and at 15 days after MDMA. Finally, brains were isolated following behavioral testing and analyzed for monoamine levels in regions of interest. One day after exposure, the rats treated with repeated 2.5 mg/kg (but not 5 mg/kg) MDMA showed mild anxiety-like behavior in the OFT but this was confounded by reduced locomotion. Anxiety-like behavior was not affected 15 days after MDMA administration. Sucrose preference increased over time but was not impacted by treatment or sex. High-pressure liquid chromatography (HPLC) analysis revealed a significant reduction in serotonin levels in the nucleus accumbens, but not prefrontal cortex or dorsal hippocampus, of rats treated with 2.5 and 5 mg/kg MDMA one day after exposure. These findings indicate that mild effects following a one-day MDMA administration at the current doses (2.5 and 5 mg/kg) may occur in both sexes, but these effects are transient. These data suggest that clinical use of MDMA at low doses may be tolerated and should not limit therapeutic usefulness.