3,4-Methylenedioxymethamphetamine increases interleukin-1beta levels and activates microglia in rat brain: studies on the relationship with acute hyperthermia and 5-HT depletion.
3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces acute hyperthermia and 5-HT release. Interleukin-1beta (IL-1beta) is a pro-inflammatory pyrogen produced by activated microglia in the brain. We examined the effect of a neurotoxic dose of MDMA on IL-1beta concentration and glial activation and their relationship with acute hyperthermia and 5-HT depletion. MDMA, given to rats housed at 22 degrees C, increased IL-1beta levels in hypothalamus and cortex from 1 to 6 h and [(3)H]-(1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)3-isoquinolinecarboxamide) binding between 3 and 48 h. Increased immunoreactivity to OX-42 was also detected. Rats became hyperthermic immediately after MDMA and up to at least 12 h later. The IL-1 receptor antagonist did not modify MDMA-induced hyperthermia indicating that IL-1beta release is a consequence, not the cause, of the rise in body temperature. When MDMA was given to rats housed at 4 degrees C, hyperthermia was abolished and the IL-1beta increase significantly reduced. The MDMA-induced acute 5-HT depletion was prevented by fluoxetine coadministration but the IL-1beta increase and hyperthermia were unaffected. Therefore, the rise in IL-1beta is not related to the acute 5-HT release but is linked to the hyperthermia. Contrary to IL-1beta levels, microglial activation is not significantly modified when hyperthermia is prevented, suggesting that it might be a process not dependent on the hyperthermic response induced by MDMA.
Orio
Laura
L
Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
O'Shea
Esther
E
Sanchez
Veronica
V
Pradillo
Jesus M
JM
Escobedo
Isabel
I
Camarero
Jorge
J
Moro
Maria A
MA
Green
A Richard
AR
Colado
M Isabel
MI
D000208:Acute Disease; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005334:Fever / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D007546:Isoquinolines / Q000493:pharmacokinetics; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000172:deficiency / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology; D013696:Temperature
D005473:Fluoxetine; D005904:Glial Fibrillary Acidic Protein; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D007546:Isoquinolines; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D012795:Sialoglycoproteins; C037850:PK 11195