5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine
María Isabel Colado, Tracey K. Murray, A.r. Green
British Journal of Pharmacology March 1, 1993 DOI: 10.1111/j.1476-5381.1993.tb12846.x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat brain |
| Interventions | Chlormethiazole Dizocilpine MDMA PCA Fenfluramine |
| Dose | MDMA 20 mg/kg, chlormethiazole 50 mg/kg or 100 mg/kg, dizocilpine 1 mg/kg, PCA 5 mg/kg or 2.5 mg/kg, fenfluramine 25 mg/kg |
| Duration | 4 days |
| Topics | MDMA Serotonin |
| Keywords | Dizocilpine P-chloroamphetamine Hippocampus Pharmacology Neurotoxicity Fenfluramine Hippocampal formation Anesthesia |
| Citations | 133 |
| Key findings | Chlormethiazole and dizocilpine prevent MDMA-induced serotonin neurotoxicity but not that from PCA or fenfluramine, indicating different mechanisms of damage. |
Abstract
1. The present study has investigated whether the neurotoxic effects of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxins, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy'), p-chloroamphetamine (PCA) and fenfluramine on hippocampal and cortical 5-HT terminals in rat brain could be prevented by administration of either chlormethiazole or dizocilpine. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in an approximate 30% loss of cortical and hippocampal 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) content 4 days later. Injection of chlormethiazole (50 mg kg-1) 5 min before and 55 min after the MDMA provided complete protection in both regions, while dizocilpine (1 mg kg-1, i.p.) protected only the hippocampus. 3. Administration of a single dose of chlormethiazole (100 mg kg-1) 20 min after the MDMA also provided complete protection to the hippocampus but not the cortex. This regime also attenuated the sustained hyperthermia (approx +2.5 degrees C) induced by the MDMA injection. 4. Injection of PCA (5 mg kg-1, i.p.) resulted in a 70% loss of 5-HT and 5-HIAA content in hippocampus and cortex 4 days later. Injection of chlormethiazole (100 mg kg-1, i.p.) or dizocilpine (1 mg kg-1, i.p.) 5 min before and 55 min after the PCA failed to protect against the neurotoxicity, nor was protection afforded by chlormethiazole when a lower dose of PCA (2.5 mg kg-1, i.p.) was given which produced only a 30% loss of 5-HT content. Chlormethiazole did prevent the hyperthermia induced by PCA (5 mg kg-1), while the lower dose of PCA (2.5 mg kg-1) did not produce a change in body temperature.5. Neither chlormethiazole nor dizocilpine prevented the neurotoxic loss of hippocampal or cortical 5-HT neurones measured 4 days following administration of fenfluramine (25 mg kg-1, i.p.).6. In general, chlormethiazole and dizocilpine were effective antagonists of the 5-HT-mediated behaviours of head weaving and forepaw treading which appeared following injection of all three neurotoxins.7. Both chlormethiazole and dizocilpine have previously been shown to prevent the neurotoxic effects ofa high dose of methamphetamine on cerebral 5-HT and dopamine pathways. These drugs also prevent MDMA-induced neurotoxicity of 5-HT pathways, but not that induced by injection of PCA or fenfluramine. This suggests that the mechanisms of neurotoxic damage to 5-HT pathways produced by substituted amphetamines cannot be identical. The monoamine loss does not appear to result from the hyperthermia produced by the neurotoxic compounds.
Comparable studies
Other experimental studies on MDMA, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin | 2000 | Experimental study | |
| Methylenedioxyamphetamine (MDA) and methylenedioxymethamphetamine (MDMA) cause selective ablation of serotonergic axon terminals in forebrain: immunocytochemical evidence for neurotoxicity Rat brain | 1988 | Experimental study | |
| The molecular mechanism of "ecstasy" [3,4-methylenedioxy-methamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced serotonin release. Human platelet plasma membrane vesicles and bovine adrenal chromaffin granule membrane... | 1992 | Laboratory study | |
| Oxytocin-dependent reopening of a social reward learning critical period with MDMA | 2019 | Experimental study | |
| Effects of certain hallucinogenic amphetamine analogs on the release of [3H]-serotonin from rat brain synaptosomes Rat whole brain synaptosomes | 1982 | Experimental study |
Citations in the library
Cited by 51
- 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
- Designer drugs: mechanism of action and adverse effects Archives of Toxicology April 1, 2020
- The pharmacology of the acute hyperthermic response that follows administration of 3,4‐methylenedioxymethamphetamine (MDMA, ‘ecstasy’) to rats British Journal of Pharmacology 2002
- A study of the neurotoxic effect of MDMA (‘ecstasy’) on 5‐HT neurones in the brains of mothers and neonates following administration of the drug during pregnancy British Journal of Pharmacology June 1, 1997
- 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
and 46 more in the library
Cites 7
- Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics 1987
- Neurotoxicity of MDMA and Related Compounds: Anatomic Studiesa Annals of the New York Academy of Sciences October 1, 1990
- The substituted amphetamines 3,4-methylenedioxymethamphetamine, methamphetamine, p-chloroamphetamine and fenfluramine induce 5-hydroxytryptamine release via a common mechanism blocked by fluoxetine and cocaine European Journal of Pharmacology May 1, 1992
- BACKWARD WALKING AND CIRCLING: BEHAVIOURAL RESPONSES INDUCED BY DRUG TREATMENTS WHICH CAUSE SIMULTANEOUS RELEASE OF CATECHOLAMINES AND 5‐HYDROXYTRYPTAMINE British Journal of Pharmacology August 1, 1979
- Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetamine. Journal of Pharmacology and Experimental Therapeutics October 1, 1988
and 2 more in the library