Behavioral and neurochemical effects of chronic methylenedioxymethamphetamine (MDMA) treatment in rhesus monkeys.
David L Frederick, S F Ali, William Slikker, Michael Gillam, R R Allen, Merle G. Paule
Neurotoxicology and Teratology September 1, 1995 DOI: 10.1016/0892-0362(95)00013-h (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | Rhesus macaques (Macaca mulatta) |
| Intervention | MDMA |
| Dose | 0.10-20.0 mg/kg, im, twice daily, for 14 consecutive days at each dose |
| Duration | 14 consecutive days at each dose during chronic treatment; neurochemical analyses 21 months after chronic treatment |
| Topics | MDMA |
| Keywords | Brain Animals Macaca mulatta Biogenic monoamines N-methyl-3,4-methylenedioxyamphetamine 3,4-dihydroxyphenylacetic acid Homovanillic acid Hydroxyindoleacetic acid Serotonin agents Conditioning, operant Reinforcement schedule Psychomotor performance Dose-response relationship, drug Drug tolerance Time factors Male |
| Key findings | Chronic escalating-dose MDMA produced tolerance to its acute behavioral effects across all operant tasks, with residual tolerance still evident afterward and least pronounced in the motivation task. Long after treatment, monkeys showed lower hippocampal 5-HIAA, serotonin uptake sites, and serotonin turnover, and higher caudate dopamine, but no significant serotonin reductions in any brain region, a pattern the authors note differs from short high-dose MDMA regimens. |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- Cognitive performance in recreational users of MDMA or 'ecstasy': evidence for memory deficits Journal of Psychopharmacology 1998
- RETRACTED: Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA ("Ecstasy") Science September 27, 2002
- Acute Effects of Dexfenfluramine (d‐FEN) and Methylenedioxymethamphetamine (MDMA) before and after Short‐Course, High‐Dose Treatment Annals of the New York Academy of Sciences May 1, 1998
- Modulation of Gut Microbiome in Ecstasy/MDMA-Induced Behavioral and Biochemical Impairment in Rats and Potential of Post-Treatment with Anacyclus pyrethrum L. Aqueous Extract to Mitigate Adverse Effects. International Journal of Molecular Sciences May 22, 2023
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Cites 9
- (±3,4-Methylenedioxymethamphetamine Selectively Damages Central Serotonergic Neurons in Nonhuman Primates JAMA July 1, 1988
- Receptor Pharmacology of MDMA and Related Hallucinogensa Annals of the New York Academy of Sciences October 1, 1990
- Acute effects of methylenedioxymethamphetamine (MDMA) on several complex brain functions in monkeys. Pharmacology, Biochemistry, and Behavior 1995
- Oral administration of 3,4-methylenedioxymethamphetamine (MDMA) produces selective serotonergic depletion in the nonhuman primate. Neurotoxicology and Teratology March 1, 1993
- 3,4-Methylenedioxymethamphetamine ("ecstasy") selectively destroys brain serotonin terminals in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics June 1, 1989
and 4 more in the library