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Behavioral and neurochemical effects of chronic methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys
D L Frederick1, S F Ali, W Slikker
1Division of Neurotoxicology, National Center for Toxicological Research/FDA, Jefferson, AR 72079-9502, USA.
Abstract:
Effects of chronic treatment with the putative serotonergic neurotoxicant MDMA were assessed in rhesus macaques using behavior in an operant test battery (OTB) designed to model aspects of time estimation, short-term memory, motivation, learning, and color and position discrimination. After an initial acute dose-response assessment, escalating doses of MDMA (0.10-20.0 mg/kg, im, twice daily, for 14 consecutive days at each dose) were administered, followed by three additional acute dose-response assessments. In general, tolerance to MDMA's acute effects was evident in all OTB tasks by the second week of repeated exposure to each individual MDMA dose and as doses escalated. Baseline OTB performance 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. Monkeys 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-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were analyzed via HPLC. Although MDMA-treated monkeys tended to have lower 5-HT concentrations in the frontal cortex, chronic MDMA treatment had no significant effects on 5-HT concentrations in any brain area sampled. Hippocampal 5-HIAA concentration, 5-HT uptake sites, and turnover of 5-HT of MDMA-treated monkeys were significantly lower than control values. DA concentrations in the CN of MDMA-treated monkeys were significantly greater than control values. No significant effects on DA concentrations were noted in any other brain area sampled. The absence of significant decreases in 5-HT and the general increase in DA concentrations are dissimilar to neurochemical effects reported after a short course of MDMA treatment at relatively high doses. These data suggest that chronic administration of gradually increasing doses of MDMA results in long-lasting tolerance to the drugs acute effects on the complex brain functions modeled in the OTB. It is uncertain, however, if such tolerance is related to the observed decreases in uptake sites and turnover of 5-HT in the hippocampus of these monkeys.
Insights
Chronic MDMA exposure in rhesus macaques led to tolerance in behavioral tasks, with lasting effects on serotonin and dopamine in specific brain regions. This suggests long-term behavioral adaptations despite neurochemical changes.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- 3,4-Methylenedioxymethamphetamine (MDMA) is a substance with known neurotoxic potential.
- Understanding the long-term effects of chronic MDMA exposure is crucial for assessing its risks.
Purpose of the Study:
- To investigate the behavioral and neurochemical consequences of chronic, escalating-dose MDMA administration in rhesus macaques.
- To assess the development of tolerance to MDMA's acute effects and any residual behavioral or neurochemical alterations.
Main Methods:
- Rhesus macaques received escalating doses of MDMA over 14 days per dose, with behavioral assessments using an operant test battery (OTB).
- Neurochemical analyses of serotonin (5-HT) and dopamine (DA) metabolites were performed on brain tissue 21 months post-treatment.
- Behavioral tasks modeled time estimation, memory, motivation, learning, and discrimination.
Main Results:
- Tolerance to MDMA's acute behavioral effects developed rapidly with repeated exposure and dose escalation.
- Baseline performance in OTB tasks was not significantly altered post-treatment, but residual tolerance was observed.
- Significant decreases in hippocampal 5-hydroxyindoleacetic acid (5-HIAA), 5-HT uptake sites, and 5-HT turnover were found.
- Dopamine (DA) concentrations were elevated in the caudate nucleus (CN) but not other brain regions.
Conclusions:
- Chronic, gradually increasing doses of MDMA induce long-lasting behavioral tolerance to its acute effects.
- Observed neurochemical changes, including reduced hippocampal 5-HT markers and increased striatal DA, may underlie these adaptations.
- The neurochemical profile differs from that seen after short-term, high-dose MDMA exposure, highlighting the impact of chronic administration patterns.