(+/-)-3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug of abuse which damages serotonin (5-HT) neurons in animals. In monkeys, the damage appears to be permanent. By contrast, in rats there is indication that neuronal recovery takes place, although there is question as to whether the recovery is sustained. The purpose of the present study was to examine the fate of 5-HT neurons in MDMA-treated rats, and to compare findings in the rat with those in the monkey. Rats were treated with MDMA (10 mg/kg i.p.) every 2 hr for a total dose of 40 mg/kg. Two, 8, 16, 32 and 52 weeks later, groups (n = 8) of MDMA-treated rats, along with age-matched controls (n = 8), were analyzed for regional brain 5-HT, 5-hydroxyindoleacetic acid and [3H]paroxetine-labeled 5-HT uptake sites. Two weeks after MDMA, 5-HT neuronal markers were reduced markedly. Reductions ranged from 42 to 82% depending on brain region. By 16 weeks, there was evidence of recovery in some brain regions (e.g., hypothalamus and striatum) and by 32 weeks, recovery was nearly complete in most brain regions examined. One year after MDMA, recovery was still evidence in all brain regions evaluated, although closer inspection of the group data revealed that whereas most MDMA-treated rats recovered, some did not. These few animals had severe and enduring serotonergic deficits in multiple brain regions. Morphologic immunocytochemical studies yielded results which corroborated the neurochemical findings.(ABSTRACT TRUNCATED AT 250 WORDS)