METHYLENEDIOXYMETHAMPHETAMINE-INDUCED SEROTONIN DEFICITS ARE FOLLOWEDBY PARTIAL RECOVERY OVER A 52-WEEK PERIOD .2. RADIOLIGAND BINDING ANDAUTORADIOGRAPHY STUDIES

In our study, age-matched Holtzman Sprague-Dawley rats (275-300 g) rec eived injections with either saline (0.9%) or 3,4-methylenedioxymetham phetamine (MDMA; 20 mg/kg free base, s.c) twice daily for 4 days and a llowed to recover for 2, 8, 16, 32 and 52 wk after the final injection before death. Radioligand binding studies with (125)l-RTl-55 to dopam ine uptake sites in striatal homogenates showed no effect of MDMA on t he density of dopamine uptake sites. In contrast, saturation binding s tudies with (125)l-RTl-55 to 5-HT uptake sites in hippocampal acid fro ntal-parietal homogenates showed a significant reduction in the number of uptake sites at 2 wk after MDMA treatment (34 and 25%, respectivel y of controls). By 16 wk, a partial recovery in the number of 5-HT upt ake sites was observed in both tissues; however, only a full recovery of serotonin uptake sites was observed in hippocampus at the end of 52 wk. In more detailed studies using autoradiography with (125)l-RTl-55 , recovery of serotonin uptake sites varied from region to region. In particular, recovery of 5-HT uptake sites in cerebral cortex was obser ved to follow a rostral-caudal gradient. In addition, recovery of 5-HT uptake site in hippocampus also followed a rostral-caudal gradient. D ifferent rates of recovery of 5-HT uptake sites were also observed for cingulate cortex, laterodorsal thalamus and ventromedial hypothalamus . No effect of MDMA was observed over lateral hypothalamus, substantia nigra and ventral tegmental area, or over serotonergic cell bodies su ch as dorsal raphe and median raphe. In conclusion, our study is consi stent with previous studies describing the selective neurotoxicity of MDMA for serotonin neurons and presents evidence showing the rate of r ecovery of 5-HT uptake sites varies according to region and that recov ery of 5-HT uptake sites in neocortex and hippocampus follows a rostra l-caudal gradient.