BEHAVIORAL AND NEUROCHEMICAL EFFECTS OF CHRONIC METHYLENEDIOXYMETHAMPHETAMINE (MDMA) TREATMENT IN RHESUS-MONKEYS

Effects of chronic treatment with the putative serotonergic neurotoxic ant MDMA were assessed in rhesus macaques using behavior in an operant test battery (OTB) designed to model aspects of time estimation, shor t-term memory, motivation, learning, and color and position discrimina tion. After an initial acute dose-response assessment, escalating dose s of MDMA (0.10-20.0 mg/kg, im, twice daily, for 14 consecutive days a t each dose) were administered, followed by three additional acute dos e-response assessments. In general, tolerance to MDMA's acute effects was evident in all OTB tasks by the second week of repeated exposure t o each individual MDMA dose and as doses escalated. Baseline OTB perfo rmance after chronic treatment was not significantly altered. Residual behavioral tolerance to MDMA's acute effects, however, was evident in all OTB tasks but was least pronounced in the motivation task. Monkey s were sacrificed (21 months after chronic treatment) and brains were dissected into several regions for neurochemical analyses. Serotonin ( 5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydro xyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were analyzed via HPLC. Although MDMA-treated monkeys tended to have lower 5-HT con centrations in the frontal cortex, chronic MDMA treatment had no signi ficant effects on 5-HT concentrations in any brain area sampled. Hippo campal 5-HIAA concentration, 5-HT uptake sites, and turnover of 5-HT o f MDMA-treated monkeys were significantly lower than control values. D A concentrations in the CN of MDMA-treated monkeys were significantly greater than control values. No significant effects on DA concentratio ns were noted in any other brain area sampled. The absence of signific ant decreases in 5-HT and the general increase in DA concentrations ar e dissimilar to neurochemical effects reported after a short course of MDMA treatment at relatively high doses. These data suggest that chro nic administration of gradually increasing doses of MDMA results in lo ng-lasting tolerance to the drugs acute effects on the complex brain f unctions modeled in the OTB. It is uncertain, however, if such toleran ce is related to the observed decreases in uptake sites and turnover o f 5-HT in the hippocampus of these monkeys.