The effects of a neurotoxic regimen of MDMA on 5HT2A receptor density, as measured through the radioligand [123-I]R91150, was examined in rats. Rats were either given 10 mg/kg MDMA s.c. or saline twice daily for 4 consecutive days. Rats were killed 6 h, 3 d or 30 d after MDMA administration. 1.85 MBq [123-I]R91150 was injected i.v. 1 h before sacrifice in all conditions (6 h, 3 d or 30 d post-drug). Amount of radioactivity was measured and compared in frontal, parietal, and occipital cortex, and in cerebellum (left hemisphere only). Amount of 5-HT and 5-HIAA in each tissue was also measured via HPLC with electrochemical detection (right hemisphere only). 6 h after MDMA, apparent 5HT2A receptor site density was decreased at all sites studied,, compared with ligand binding in saline-treated rats. When measured 3 d post-MDMA, [123-I]R91150 binding density was significantly lower than ligand binding in saline-treated rats, but [123-I]R91150 binding tended to be lower globally. However, [123-I]R91150 binding was either comparable to or higher than binding in control rats when compared 30 days post-drug. Levels of 5-HT were decreased in frontal and occipital areas 6 h after MDMA, compared with 5-HT levels in saline-treated rats, and brain 5-HIAA was globally decreased at this time point. Concentrations of 5-HT and 5-HIAA in brain were lower in rats killed 3 days after MDMA than in saline-treated controls, with reductions seen in all areas save parietal tissue. Rats killed 30 days after MDMA also had 5-HT and 5-HIAA levels that were lower than controls in all brain regions. A scatterplot of binding against 5-HT content indicated that an increase in [123-I]R91150 binding was associated with greater reduction of 5-HT, measured as percentage of control value. Findings in rats were also compared with SPECT scans of current and abstinent ecstasy users (see description of study in "Human Studies, User/Non-user Comparisons." The authors used the collection of findings to suggest that changes in 5HT2A receptor density could be produced by changes brain 5-HT content, and that the increase in 5-HT2A site density arising after initial decrease may be a compensatory mechanism occurring in response to lower levels of 5-HT in brain. However, extrapolating from rat data would also suggest that increased 5HT2A receptor density is associated with a loss of serotonergic function of up to 80%. This relatively high level of serotonin depletion seems incongruent with the subtle changes in brain function and cognitive deficit seen in ecstsy users.