Evidence that MDMA ('ecstasy') increases interleukin-1ß levels in rat brain 1L. Orio, 1V. Sanchez,1E. O'Shea, 1J. Camarero,1I. Escobedo,2A.R. Green & 1M.I. Colado. 1Dept. Farmacol., F. Medicina, Univ. Complutense, 28040 Madrid, Spain & 2School of Pharmacy, De Montfort Univ., Leicester, LE1 9BH.

Print abstract Search PubMed for: Orio L Sanchez V O'Shea E Camarero J Escobedo I Green AR Colado MI

Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that, in the brain, is mainly produced by activated microglia (Chauvet et al., 2001). IL-1ßis a key factor in the febrile response to pyrogens (Luheshi et al., 1999) and a mediator of several forms of brain damage in rodents (Pearson et al., 1999; Touzani et al., 1999). Administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') to rats produces a long-term degeneration of 5-HT nerve endings in the brain and an acute hyperthermic response which is involved in the neuronal damage (Colado et al., 1998).

We have now examined the time-course of changes induced by MDMA on the concentration of IL-1ß in the cortex and hypothalamus of the rat and investigated whether these changes are related to the hyperthermic and neurotoxic responses induced by the drug.

Male Dark Agouti rats (175-200g) received MDMA (12.5 mg kg^-1, i.p.) or saline when housed at a room temperature of 22ºC. Animals were sacrificed 1 h, 3 h, 6 h, 12 h, 24 h and 7 days later and the levels of IL-1ß measured by ELISA (Simi et al., 2002). In another study, rats were maintained at 4ºC, for 4 h before and up to 6 h after MDMA administration and sacrificed either 3 h or 7 days after drug injection. Rectal temperature was measured throughout. The 5-HT content of the cortex was measured by h.p.l.c. 7 days after MDMA injection.

A pronounced increase in IL-1ß levels in the hypothalamus and cortex was observed 1 h, 3 h and 6 h after MDMA administration with the highest levels occurring at 3 h in the hypothalamus and at 3 and 6 h in the cortex (Figure 1). No change was observed 12 h, 24 h and 7 days after MDMA injection in either brain area. The increase in IL-1ß induced by MDMA at 22ºC (814% in hypothalamus, 219% in cortex) was significantly reduced, though not abolished, when rats were kept at 4ºC (454% in hypothalamus, 142% in cortex). In these rats the hyperthermic response was totally abolished and the long-term loss in cortical 5-HT concentration significantly attenuated.

These findings indicate that immediately after MDMA there is an acute increase in the brain IL-1ß concentration which is, to some extent, a consequence of the hyperthermia and suggest that IL-1ß may play an important role in the neurotoxicity of the drug.

Figure 1. Time-course of changes in IL-1ß levels in the hypothalamus and cortex induced by MDMA (12.5 mg kg^-1, i.p.). Results shown as mean ± s.e.mean, n=6-8. Different from the corresponding saline-treated group: ^fP<0.01, *P<0.001.

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Pearson, V.L. et al., (1999) Glia 25, 311-323.
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M.I.C. thanks MCYT (SAF2001-1437) and FIS (02/1885) for financial support.