A study of the mechanism of MDMA (‘Ecstasy’)‐induced neurotoxicity of 5‐HT neurones using chlormethiazole, dizocilpine and other protective compounds
María Isabel Colado, A.r. Green
British Journal of Pharmacology 1994 DOI: 10.1111/j.1476-5381.1994.tb14034.x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rats |
| Interventions | MDMA gamma-butyrolactone pentobarbitone ondansetron chlormethiazole dizocilpine p-chloroamphetamine |
| Dose | 20 mg kg-1 MDMA, 400 mg kg-1 gamma-butyrolactone, 25 mg kg-1 pentobarbitone, 0.5 mg kg-1 or 0.1 mg kg-1 ondansetron, 50 mg kg-1 chlormethiazole, 1 mg kg-1 dizocilpine, 2.5 mg kg-1 p-chloroamphetamine |
| Duration | 4 days for long-term effect, 4 hours for acute effect |
| Topics | MDMA Serotonin |
| Keywords | Dizocilpine Pharmacology Neurotoxicity Dopamine Neurotoxin Anesthesia |
| Citations | 62 |
| Key findings | Gamma-butyrolactone and pentobarbitone protect against MDMA-induced serotonin neurotoxicity in rats, but ondansetron does not, and protection appears unrelated to blocking initial serotonin release. |
Abstract
1. An investigation has been made in rats into the neurotoxic effect of the relatively selective 5-hydroxytryptamine (5-HT) neurotoxin, 3,4-methylenedioxymethamphetamine (MDMA or 'Ecstasy') using chlormethiazole and dizocilpine, both known neuroprotective compounds and also gamma-butyrolactone, ondansetron and pentobarbitone. 2. Administration of MDMA (20 mg kg-1, i.p.) resulted in a 50% loss of cortical and hippocampal 5-HT and 5-hydroxyindole acetic acid (5-HIAA) 4 days later. This reflects the long term neurotoxic loss of 5-HT that occurs. Injection of gamma-butyrolactone (GBL; 400 mg kg-1, i.p.) 5 min before and 55 min after the MDMA provided substantial protection. Pentobarbitone (25 mg kg-1, i.p.) using the same dose regime was also protective, but ondansetron (0.5 mg kg-1 or 0.1 mg kg-1, i.p.) was without effect. 3. MDMA (20 mg kg-1) had no significant effect on striatal dopamine concentration 4 days later but did produce a small decrease in 3,4-dihydroxyphenylacetic acid (DOPAC) content. There were few significant changes in rats given MDMA plus GBL, ondansetron or pentobarbitone. 4. A single injection of MDMA (20 mg kg-1, i.p.) resulted in a greater than 80% depletion of 5-HT in hippocampus and cortex 4 h later, reflecting the initial rapid release that had occurred. None of the neuroprotective compounds (chlormethiazole, 50 mg kg-1; dizocilpine, 1 mg kg-1; GBL, 400 mg kg-1; pentobarbitone, 25 mg kg-1) given 5 min before and 55 min after the MDMA injection, altered the degree of 5-HT loss. 5. Acute MDMA injection increased striatal dopamine content (28%) and decreased the DOPAC content. In general, administration of the drugs under investigation did not significantly alter these MDMA-induced changes. Both chlormethiazole and GBL produced a greater increase in dopamine than MDMA alone, but this was apparently an additive effect to the action of either drug alone. 6. The 5-HT loss 4 h following administration of the neurotoxin p-chloroamphetamine (2.5 mg kg-1,i.p.) was not affected by chlormethiazole or dizocilpine. p-Chloroamphetamine did not appear to alter striatal dopamine metabolism.7. None of the protective drugs inhibited the initial 5-HT loss following MDMA, rendering unlikely any proposal that they are protective because they inhibit 5-HT release and the subsequent formation ofa toxic indole derivative. All the protective compounds (unlike ondansetron) probably inhibit dopamine release in the striatum. Since the neurotoxic action of some substituted amphetamines is dependent on the integrity of nigro-striatal neurones, this fact may go some way to explain the protective action of this diverse group of compounds.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 21
- 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
- The hyperthermic and neurotoxic effects of ‘Ecstasy’ (MDMA) and 3,4 methylenedioxyamphetamine (MDA) in the Dark Agouti (DA) rat, a model of the CYP2D6 poor metabolizer phenotype British Journal of Pharmacology August 1, 1995
- Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration British Journal of Pharmacology February 1, 1999
and 16 more in the library
Cites 8
- 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
- 5‐HT loss in rat brain following 3, 4‐methylenedioxymethamphetamine (MDMA), p‐chloroamphetamine and fenfluramine administration and effects of chlormethiazole and dizocilpine British Journal of Pharmacology March 1, 1993
- Amphetamine derivatives induce locomotor hyperactivity by acting as indirect serotonin agonists. Psychopharmacology 1991
- MDMA (ecstasy) effects on cultured serotonergic neurons: evidence for Ca2+-dependent toxicity linked to release Brain Research February 1, 1990
and 3 more in the library