3,4-Methylenedioxymethamphetamine increases pro-interleukin-1beta production and caspase-1 protease activity in frontal cortex, but not in hypothalamus, of Dark Agouti rats: role of interleukin-1beta in neurotoxicity.
3,4-Methylenedioxymethamphetamine (ecstasy) increases mature interleukin-1beta production in rat brain shortly after injection. This effect is a consequence of the 3,4-methylenedioxymethamphetamine-induced hyperthermia and is reduced when rats are maintained at low ambient room temperature. Since interleukin-1beta is generated as an inactive 31-kDa precursor protein and processed into mature form by caspase-1, we have now examined the effect of 3,4-methylenedioxymethamphetamine on pro-interleukin-1beta production and caspase-1-like protease activity in the hypothalamus and frontal cortex of Dark Agouti rats. 3,4-Methylenedioxymethamphetamine increased the immunoreactivity of pro-interleukin-1beta in frontal cortex, not in hypothalamus, 3 h and 6 h after administration. Caspase-1-like protease activity was increased in frontal cortex 3 h after 3,4-methylenedioxymethamphetamine injection compared with saline-treated animals. 3,4-Methylenedioxymethamphetamine did not modify the expression of pro-caspase-1 but increased the immunoreactivity for the caspase-1 active cleavage product (p20) in frontal cortex 3 h after dosing. No change on caspase-1-like protease activity was observed in hypothalamus. The basal immunoreactivity of pro-interleukin-1beta and caspase-1-like protease activity was higher in the hypothalamus than in frontal cortex of control (saline-treated) animals. These data indicate that 3,4-methylenedioxymethamphetamine alters, in a region-specific manner, the mechanisms which regulate interleukin-1beta production in the brain of Dark Agouti rats and suggest that the release of interleukin-1beta in hypothalamus may be regulated independently of caspase-1 activation. Administration (i.c.v.) of interleukin-1beta enhanced the 3,4-methylenedioxymethamphetamine-induced long-term loss of brain 5-HT parameters and immediate hyperthermia. Neither of these effects was observed when interleukin-1beta was given into hippocampus. These results indicate that exogenous interleukin-1beta potentiates 3,4-methylenedioxymethamphetamine neurotoxicity as a consequence of its effect on body temperature and suggest that the 3,4-methylenedioxymethamphetamine-induced rise in interleukin-1beta levels could in turn contribute to the maintenance of 3,4-methylenedioxymethamphetamine-induced hyperthermia and subsequent neurotoxicity.
O'Shea
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Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid 28040, Spain.
Sanchez
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Orio
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Escobedo
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Green
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Colado
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D000818:Animals; D015153:Blotting, Western; D020170:Caspase 1 / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D005334:Fever / Q000139:chemically induced / Q000503:physiopathology; D005625:Frontal Lobe / Q000187:drug effects* / Q000378:metabolism; D006213:Hallucinogens / Q000633:toxicity*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010447:Peptide Hydrolases / Q000187:drug effects* / Q000378:metabolism; D011498:Protein Precursors / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism
D006213:Hallucinogens; D007375:Interleukin-1; D011498:Protein Precursors; C043830:interleukin 1 precursor; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D010447:Peptide Hydrolases; D020170:Caspase 1; D018817:N-Methyl-3,4-methylenedioxyamphetamine