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Neurochemical and neurohistological alterations in the rat and monkey produced by orally administered
W Slikker1, S F Ali, A C Scallet
1Pharmacodynamics Branch, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Abstract:
MDMA is an amphetamine analog prescribed by some health professionals in the field of psychotherapy and used as a recreational drug by the general public. In recent reports, investigators have suggested that MDMA produces acute neurotoxicity when administered by subcutaneous injection. In order to determine if MDMA produces lasting neurochemical alterations after oral administration, groups of six rats (adult male Sprague-Dawley) were dosed by gavage with either 40 or 80 mg/kg of MDMA or saline vehicle once every 12 hr for 4 days. These rats were terminated 2 weeks after the first dose along with an additional group of rats (80 mg/kg) terminated 4 weeks after the first dose. Brain regions including the hippocampus (H), caudate nucleus (CN), hypothalamus (HY), frontal cortex (FC), and brain stem (BS) were analyzed by HPLC with electrochemical detection for concentrations of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and norepinephrine (NE). In the CN, 40 mg/kg MDMA produced no change in DA, DOPAC, or HVA, but a 50-60% decrease in 5-HT and 5-HIAA concentrations was observed at 2 weeks. Similar effects were observed at 80 mg/kg at both 2 weeks and 4 weeks. A temporary decrease was also seen in DA (21%) and in HVA (34%) 2 weeks but not 4 weeks after the 80 mg/kg dose regimen. In the H, MDMA (40 or 80 mg/kg) produced no change in NE, but a 50-60% decrease was seen in 5-HT and 5-HIAA concentrations at 2 weeks. Concentrations of 5-HT and 5-HIAA were significantly decreased in the HY and FC by all MDMA treatments, but DA and DOPAC concentrations were not altered as compared to vehicle controls. BS was least affected by treatment with no change in DA, DOPAC, or 5-HIAA concentrations and only a slight decrease in 5-HT (19-33%) concentrations at 2 weeks but not at 4 weeks. To determine the sensitivity of the nonhuman primate to MDMA, a total of nine rhesus monkeys were dosed with vehicle or 5 or 10 mg/kg MDMA (n = 3) by gastric intubation twice per day for 4 days. One month after MDMA dosing, a dose-related reduction from vehicle control values for 5-HT and 5-HIAA was observed. These results indicate that the monkey may be more sensitive than the rat to the persistent serotonergic neurotoxicity of MDMA.(ABSTRACT TRUNCATED AT 400 WORDS)
Insights
MDMA (3,4-methylenedioxymethamphetamine) oral administration causes lasting neurochemical changes, particularly a significant decrease in serotonin levels in rat brain regions. Nonhuman primates showed greater sensitivity to MDMA
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- MDMA (3,4-methylenedioxymethamphetamine) is used in psychotherapy and recreationally.
- Concerns exist regarding MDMA's potential for acute neurotoxicity via injection.
- This study investigates lasting neurochemical alterations following oral MDMA administration.
Purpose of the Study:
- To determine if oral MDMA administration causes persistent neurochemical changes in rats.
- To compare the neurotoxic effects of MDMA in rats and nonhuman primates.
- To assess dose- and time-dependent neurochemical alterations in specific brain regions.
Main Methods:
- Rats were orally administered MDMA (40 or 80 mg/kg) or saline every 12 hours for 4 days.
- Brain regions (hippocampus, caudate nucleus, hypothalamus, frontal cortex, brain stem) were analyzed via HPLC.
- Neurotransmitter concentrations (dopamine, serotonin, norepinephrine) and their metabolites were measured at 2 and 4 weeks post-administration.
- Rhesus monkeys were dosed with MDMA (5 or 10 mg/kg) or vehicle, with analyses conducted one month later.
Main Results:
- Oral MDMA caused significant, long-lasting decreases in serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in the caudate nucleus, hippocampus, hypothalamus, and frontal cortex of rats.
- A temporary decrease in dopamine (DA) and homovanillic acid (HVA) was observed in the caudate nucleus of rats after high-dose MDMA.
- Nonhuman primates exhibited a dose-related reduction in 5-HT and 5-HIAA, suggesting greater sensitivity to MDMA's serotonergic neurotoxicity compared to rats.
Conclusions:
- Oral MDMA administration induces persistent serotonergic neurotoxicity in rats.
- The brain stem is relatively resistant to MDMA's neurotoxic effects.
- Nonhuman primates appear more sensitive than rats to the long-term serotonergic neurotoxic effects of MDMA.