PMID- 11351932
OWN - NLM
STAT- MEDLINE
DCOM- 20010920
LR  - 20190726
IS  - 0033-3158 (Print)
IS  - 0033-3158 (Linking)
VI  - 154
IP  - 3
DP  - 2001 Mar
TI  - 3,4-Methylenedioxymethamphetamine induces monoamine release, but not toxicity, 
      when administered centrally at a concentration occurring following a peripherally 
      injected neurotoxic dose.
PG  - 251-60
AB  - RATIONALE: There is good evidence that 3,4-methylenedioxymethamphetamine 
      (MDMA)-induced neurotoxicity results from free radical formation. However, it is 
      unclear whether it is the presence of MDMA or a metabolite in the brain that 
      initiates this process. OBJECTIVE: We wished to measure the concentration of MDMA 
      in the brain following peripheral administration of neurotoxic doses and examine 
      the effect on acute monoamine release and the subsequent neurotoxic loss in 
      5-hydroxytryptamine (5-HT) content when a high concentration of MDMA was infused 
      into cerebral tissue. METHODS: Selectively placed microdialysis probes were used 
      to determine both the concentration of MDMA in the brain following peripheral 
      injection and the degree of 5-HT release. Monoamines in dialysate and tissue were 
      measured with standard HPLC techniques. RESULTS: MDMA, administered 
      intraperitoneally, at doses of 10 and 15 mg/kg, which produce neurodegeneration, 
      resulted in an estimated cerebral extracellular concentration of MDMA of 11 and 
      20 microM, respectively. When MDMA (100-400 microM) was perfused through a 
      selectively placed microdialysis probe it dose-dependently increased 5-HT release 
      in the hippocampus and dopamine release in the striatum. Seven days after 
      perfusion of MDMA the concentration of 5-HT and its metabolite, 
      5-hydroxyindoleacetic acid was unchanged in the ipsilateral side of the brain of 
      normothermic rats and also in the brains of animals made hyperthermic to mimic 
      the acute effect of MDMA given peripherally. In contrast, perfusion with 
      5,7-dihydroxytryptamine (400 microM) markedly decreased the cerebral 5-HT 
      content. A second probe, also placed in the hippocampus at a distance of 1 mm 
      from the main probe, revealed that during the perfusion of MDMA (400 microM) the 
      estimated extracellular concentration of MDMA in the hippocampus was between 10.4 
      and 19.5 microM, i.e. in the range of concentrations observed after systemic 
      injection of neurotoxic doses of MDMA. CONCLUSIONS: These data demonstrate that 
      MDMA when injected directly into the brain produces 5-HT release but no 
      neurotoxicity, suggesting that it must be metabolised peripherally in order to 
      produce compounds that induce free radical formation and neurotoxicity in the 
      brain.
FAU - Esteban, B
AU  - Esteban B
AD  - Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, 
      28040 Madrid, Spain.
FAU - O'Shea, E
AU  - O'Shea E
FAU - Camarero, J
AU  - Camarero J
FAU - Sanchez, V
AU  - Sanchez V
FAU - Green, A R
AU  - Green AR
FAU - Colado, M I
AU  - Colado MI
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Psychopharmacology (Berl)
JT  - Psychopharmacology
JID - 7608025
RN  - 0 (Biogenic Monoamines)
RN  - 0 (Serotonin Agents)
RN  - 102-32-9 (3,4-Dihydroxyphenylacetic Acid)
RN  - 333DO1RDJY (Serotonin)
RN  - 54-16-0 (Hydroxyindoleacetic Acid)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
RN  - VTD58H1Z2X (Dopamine)
RN  - X77S6GMS36 (Homovanillic Acid)
SB  - IM
MH  - 3,4-Dihydroxyphenylacetic Acid/metabolism
MH  - Animals
MH  - Biogenic Monoamines/*metabolism
MH  - Dopamine/metabolism
MH  - Hippocampus/*drug effects/metabolism
MH  - Homovanillic Acid/metabolism
MH  - Hydroxyindoleacetic Acid/metabolism
MH  - Injections, Intraventricular
MH  - Male
MH  - Microdialysis
MH  - N-Methyl-3,4-methylenedioxyamphetamine/*administration & dosage/metabolism
MH  - Perfusion
MH  - Rats
MH  - Serotonin/*metabolism
MH  - Serotonin Agents/*administration & dosage/metabolism
EDAT- 2001/05/16 10:00
MHDA- 2001/09/21 10:01
CRDT- 2001/05/16 10:00
PHST- 2001/05/16 10:00 [pubmed]
PHST- 2001/09/21 10:01 [medline]
PHST- 2001/05/16 10:00 [entrez]
AID - 10.1007/s002130000645 [doi]
PST - ppublish
SO  - Psychopharmacology (Berl). 2001 Mar;154(3):251-60. doi: 10.1007/s002130000645.