Synapse
October 1, 1995
Jean Lud Cadet, Bruce Ladenheim, Hiroshi Hirata et al.
81 citations
Mice carrying extra copies of the human superoxide dismutase gene are protected against MDMA-induced damage to brain dopamine neurons. Normal mice showed large drops in striatal dopamine and its metabolite DOPAC one day and two weeks after a single MDMA injection. Mice with one copy of the transgene showed dopamine loss only at one day, while mice with two copies showed no loss at either time point. Three repeated injections caused dopamine loss in normal mice, small losses in one-copy mice, and no loss in two-copy mice. Serotonin levels were unaffected in all groups. The findings indicate that superoxide radicals contribute to MDMA's dopamine toxicity.
International Journal of Developmental Neuroscience
June 5, 2004
Jerrold S. Meyer, Mark Grande, Kenneth M. Johnson et al.
50 citations
MDMA damages fine serotonergic fibers and nerve terminals in adult organisms, while developing animals appear less susceptible, possibly due to a lack of drug-induced hyperthermia. In neonatal rats given MDMA from postnatal days 1–4, hyperthermia was produced in some groups, but all effects were independent of body temperature. The hippocampus showed significant reductions in serotonergic markers at postnatal days 25 and 60, but no effect at 9 months. However, reduced fiber density occurred in two neocortical areas, and hyperinnervation appeared in the caudate-putamen and nucleus accumbens shell. MDMA also caused a two-fold increase in cleaved caspase-3-immunoreactive cells in the rostral forebrain and hippocampus, indicating apoptotic cell death and long-term reorganization of forebrain serotonergic innervation. Offspring of MDMA-using women may face heightened risk for abnormal neural and behavioral development.
Annals of the New York Academy of Sciences
June 1, 2002
B. Gough, Syed Z. Imam, Bruce E. Blough et al.
47 citations
Paramethoxyamphetamine (PMA), a drug sold illicitly as 'ecstasy' and linked to fatalities in Australia and the United States, produces neurotoxic effects on dopamine and serotonin systems in rats similar to MDMA and methamphetamine (METH). Extracellular levels of dopamine, its metabolites DOPAC and HVA, serotonin (5-HT), and its metabolite 5-HIAA were measured in the caudate of freely moving rats via microdialysis. METH (2.5 mg/kg) increased dopamine 700% and decreased DOPAC 30% and HVA 50%, with no serotonin changes. MDMA (10 and 20 mg/kg) increased dopamine up to 950% and serotonin up to 575%.
Annals of the New York Academy of Sciences
August 1, 2006
Jerrold S. Meyer, Matthew E. Brevard, Brian J. Piper et al.
40 citations
A recreational dose of MDMA (1 mg/kg) activates multiple brain regions in marmoset monkeys, including the midbrain raphe nuclei, hippocampus, hypothalamus, amygdala, and the corticostriatal circuit (dorsal thalamus, sensory motor cortex, and basal ganglia). MDMA also activates the primary visual cortex and enhances the visual cortical response to light. The onset of brain activation matches the rise in plasma MDMA levels. A second study found that both low (4 × 1 mg/kg oral) and high (4 × 10 mg/kg intramuscular) MDMA doses reduce the NAA/creatine ratio in the hypothalamus, indicating vulnerability to damage. High doses also cause prolonged hyperthermia and reductions in serotonin and serotonin transporters in several brain areas, suggesting even recreational doses may have adverse consequences.
Annals of the New York Academy of Sciences
May 1, 1998
David Frederick, Syed F. Ali, Michael Gillam et al.
32 citations
In rhesus monkeys, the acute behavioral effects of MDMA and dexfenfluramine (d-FEN) were assessed using five food-reinforced tasks measuring learning, memory, attention, time estimation, motivation, and discrimination. After a short-course, high-dose exposure to MDMA (10 mg/kg twice daily for four days), monkeys became less sensitive to the acute behavioral disruption by both drugs, especially d-FEN, and this tolerance was task-specific. In contrast, monkeys similarly exposed to high-dose d-FEN (5 mg/kg) showed no change in sensitivity. Surprisingly, both groups showed similar neurochemical effects—approximately 50% decreases in serotonin in the frontal cortex and hippocampus six months later—yet only MDMA pretreatment induced behavioral tolerance.
Annals of the New York Academy of Sciences
October 1, 2004
Yossef Itzhak, Karen L. Anderson, Syed F. Ali
31 citations
Mice lacking the neuronal nitric oxide synthase (nNOS) gene are resistant to methamphetamine-induced psychomotor sensitization and dopaminergic neurotoxicity, but not to serotonin-mediated effects of MDMA (Ecstasy). Repeated MDMA administration caused psychomotor sensitization in both normal and nNOS knockout mice, while methamphetamine caused sensitization only in normal mice. Sensitization to both drugs persisted for 40 days in normal mice but not in knockouts. High-dose MDMA depleted serotonin in several brain regions of both types, indicating nNOS absence does not protect against serotonin loss. Striatal dopamine neurotoxicity from high-dose MDMA and methamphetamine was partially prevented in knockouts given MDMA and fully prevented in knockouts given methamphetamine. The nNOS gene is required for dopamine-mediated effects of both drugs but not for serotonin-mediated effects of MDMA.
Annals of the New York Academy of Sciences
June 1, 2002
Jerrold S. Meyer, Syed F. Ali
25 citations
The drug MDMA (ecstasy) damages serotonin-producing nerve fibers in adult animals, but developing animals appear less vulnerable. One hypothesis was that newborns lack the drug-induced fever that contributes to damage. This experiment tested that by inducing hyperthermia in newborn rats for two hours after each MDMA injection from postnatal day 1 to 4, while keeping other litters at normal body temperature. Even without elevated temperature, MDMA caused significant reductions in serotonin transporter binding and serotonin levels in the hippocampus by day 25, and the deficit persisted to day 60. The neocortex showed no effect at day 25 but significant damage by day 60. MDMA can damage the developing brain even without hyperthermia, and recovery may be less complete than in adults.
Annals of the New York Academy of Sciences
May 1, 1998
Michael H. Baumann, Richard B. Rothman, Syed F. Ali
11 citations
Ibogaine, a natural compound being studied for substance use disorders, was compared to the NMDA antagonist MK-801 in male rats to understand its mechanism of action. Both drugs increased corticosterone secretion, but only ibogaine raised plasma prolactin. Ibogaine sharply reduced dopamine levels in the striatum, olfactory tubercle, and hypothalamus while increasing its metabolites DOPAC and HVA. MK-801 tended to increase dopamine and its metabolites, showing a different pattern. Neither drug affected serotonin systems. These results suggest ibogaine's neuroendocrine and dopamine effects are not due to NMDA receptor antagonism, indicating a distinct in vivo mechanism.