PMID- 7682129
OWN - NLM
STAT- MEDLINE
DCOM- 19930513
LR  - 20190512
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 108
IP  - 3
DP  - 1993 Mar
TI  - 5-HT loss in rat brain following 3,4-methylenedioxymethamphetamine (MDMA), 
      p-chloroamphetamine and fenfluramine administration and effects of 
      chlormethiazole and dizocilpine.
PG  - 583-9
AB  - 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.
FAU - Colado, M I
AU  - Colado MI
AD  - Astra Neuroscience Research Unit, London.
FAU - Murray, T K
AU  - Murray TK
FAU - Green, A R
AU  - Green AR
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0C5DBZ19HV (Chlormethiazole)
RN  - 2DS058H2CF (Fenfluramine)
RN  - 333DO1RDJY (Serotonin)
RN  - 4764-17-4 (3,4-Methylenedioxyamphetamine)
RN  - 54-16-0 (Hydroxyindoleacetic Acid)
RN  - 64-12-0 (p-Chloroamphetamine)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - 3,4-Methylenedioxyamphetamine/*analogs & derivatives/antagonists & 
      inhibitors/pharmacology/toxicity
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Body Temperature/drug effects
MH  - Brain Chemistry/*drug effects
MH  - Cerebral Cortex/drug effects/metabolism
MH  - Chlormethiazole/*pharmacology
MH  - Dizocilpine Maleate/*pharmacology
MH  - Fenfluramine/antagonists & inhibitors/*pharmacology/toxicity
MH  - Hippocampus/drug effects/metabolism
MH  - Hydroxyindoleacetic Acid/metabolism
MH  - Male
MH  - N-Methyl-3,4-methylenedioxyamphetamine
MH  - Rats
MH  - Serotonin/*metabolism
MH  - p-Chloroamphetamine/antagonists & inhibitors/*pharmacology/toxicity
PMC - PMC1908028
EDAT- 1993/03/01 00:00
MHDA- 1993/03/01 00:01
PMCR- 1994/03/01
CRDT- 1993/03/01 00:00
PHST- 1993/03/01 00:00 [pubmed]
PHST- 1993/03/01 00:01 [medline]
PHST- 1993/03/01 00:00 [entrez]
PHST- 1994/03/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.1993.tb12846.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 1993 Mar;108(3):583-9. doi: 10.1111/j.1476-5381.1993.tb12846.x.