Behavioural, hyperthermic and neurotoxic effects of 3,4-methylenedioxymethamphetamine analogues in the Wistar rat.
E D O'Loinsigh, G Boland, J P Kelly, K M O'Boyle
Progress in Neuro-Psychopharmacology and Biological Psychiatry April 2001 DOI: 10.1016/s0278-5846(00)00179-2 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Young adult male Wistar rats and rat forebrain synaptosomal preparations |
| Interventions | MDMA MDEA MDBA |
| Dose | 20 mg/kg i.p. acute and repeated (8 x 20 mg/kg i.p., twice daily for 4 days); in vitro concentrations up to 100 microM |
| Duration | 4 days of dosing with assessment at 14 days post-treatment |
| Measures | open-field locomotion, rearing, stereotypy, Straub tail, head weaving, aural temperature, [3H]paroxetine binding, forebrain 5-HT and 5-HIAA concentrations, [3H]5-HT and [3H]DA release |
| Topics | MDMA |
| Key findings | MDMA and MDEA, but not MDBA, induced acute behavioral changes, hyperthermia, and long-term serotonergic neurotoxicity. The authors argue that both acute hyperthermia and increased neurotransmitter release are required for neurotoxic damage, as neither effect alone suffices. |
Abstract
1. The ability of N-ethyl (MDEA) and N-butyl (MDBA) analogues of 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') to induce acute behavioural changes and increases in body temperature, and to cause serotonergic neurotoxicity, was assessed in young adult male Wistar rats. The in vitro ability of MDMA analogues to evoke presynaptic monoamine release from crude rat forebrain synaptosomal preparations pre-labelled with [3H]5-HT or [3H]DA was also measured. 2. In behavioural experiments, acute MDMA and MDEA (20 mg/kg, i.p.) significantly increased rat open-field locomotion scores, decreased open-field rearing, and induced stereotypy, Straub tail and head weaving. MDBA did not produce any of these behaviours. 3. After repeated dosing (8 x 20 mg/kg, i.p., twice daily for 4 days), MDMA > MDEA >> MDBA > or = saline at decreasing forebrain [3H]paroxetine binding levels and concentrations of 5-HT and 5-HIAA at 14 days post-treatment. None of the analogues caused any long-term changes in dopamine or noradrenaline concentrations in the forebrain. 4. Acute MDMA and MDEA (20 mg/kg, i.p.) produced significant acute increases in rat aural temperature compared with saline-treated animals, while 20 mg/kg MDBA caused no significant effects. 5. MDA, MDMA and MDEA were equipotent at inducing [3H]5-HT release from frontal cortex/hippocampal synaptosomes, while MDBA only evoked a significant release at 100 microM concentrations. The potency order for inducing [3H]DA release from striatal synaptosomes was MDA > MDMA > MDEA = MDBA. 6. This study shows that large N-alkyl substitution decreases the ability of MDMA analogues to evoke presynaptic 5-HT and DA release, induce acute hyperthermia, hyperlocomotion and behavioural changes, and cause long-term serotonergic neurotoxicity. 7. The structure-activity relationship data presented here indicate that the neurotoxic damage caused by substituted amphetamines requires a combination of acute hyperthermia and increased neurotransmitter release. Induction of one of these effects in isolation is not sufficient to cause serotonergic nerve terminal degradation.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
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- Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy Journal of Psychopharmacology September 10, 2020
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Cites 28
- Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Journal of Neuroscience August 1, 1988
- 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Journal of Pharmacology and Experimental Therapeutics September 1, 1987
- Hallucinogenic Amphetamine Selectively Destroys Brain Serotonin Nerve Terminals Science September 6, 1985
- Small Changes in Ambient Temperature Cause Large Changes in 3,4-Methylenedioxymethamphetamine (MDMA)-Induced Serotonin Neurotoxicity and Core Body Temperature in the Rat Journal of Neuroscience July 1, 1998
- In vivo evidence for free radical involvement in the degeneration of rat brain 5‐HT following administration of MDMA (‘ecstasy’) and p‐chloroamphetamine but not the degeneration following fenfluramine British Journal of Pharmacology July 1, 1997
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