Intracerebroventricular interleukin-1ß exarcebates MDMA-induced neurotoxicity by an additive effect on rectal temperature   1E. O'Shea, 1L. Orio, 1J. Camarero, 1I. Escobedo, 1V. Sanchez, 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: O'Shea E Orio L Camarero J Escobedo I Sanchez V Green AR Colado MI

3,4-Methylenedioxymethamphetamine (MDMA or 'ecstasy') produces a long-term degeneration of 5-HT nerve endings in the rat brain and an acute hyperthermic response which is involved in the neuronal damage (Green et al., 1995; Colado et al., 1998). Administration of MDMA to rats induces an acute increase in the brain levels of interleukin-1ß (IL-1ß) which is partially dependent on the hyperthermic response induced by the drug (this Meeting). IL-1ß appears to directly mediate several forms of neuronal damage and when administered in the brain potentiates ischaemic and excitotoxic brain damage (Stroemer & Rothwell, 1998; Grundy et al., 1999). We have now examined the ability of IL-1ß, administered i.c.v., to potentiate the long-term loss of 5-HT nerve terminals induced by MDMA and establish whether this effect is related to changes in the hyperthermic response.

Male Dark Agouti rats (175-200g) received IL-1ß (5 ng, i.c.v) or sterile vehicle (5 µl over 5 min) 30 min before MDMA (7 mg kg^-1, i.p.) or saline at room temperature (22ºC). Rectal temperature was measured throughout. Animals were sacrificed 7 days later and the levels of 5-HT in cortex and hippocampus and 5-HT transporter density in the cortex determined by h.p.l.c and [³H]paroxetine binding, respectively.

MDMA produced no change in ipsilateral cortical 5-HT levels but in the presence of IL-1ß there was a significant reduction in this parameter (Figure 1). Similar results were obtained in the ipsilateral hippocampus. In addition, MDMA caused a significant loss in ipsilateral cortical [³H]paroxetine binding which was also augmented by IL-1ß pretreatment. These results were paralleled in the contralateral side. The overall hyperthermic response induced by MDMA was increased in animals pretreated with IL-1ß such that although the peak temperature was similar in both groups, the hyperthermia was maintained above that of MDMA-treated rats for at least 6 h after. IL-1ß alone also produced a significant increase in rectal temperature but did not alter either of the 5-HT parameters.These findings indicate that IL-1ß, when given i.c.v., exacerbates the long-term 5-HT brain damage induced by MDMA and that this effect is probably due to an additive effect of the cytokine and MDMA on rectal temperature.

Figure 1. Effect of IL-1ß (5 ng, i.c.v.) on MDMA (7 mg kg^-1, i.p.)-induced long-term changes (% of control) in ipsilateral cortical 5-HT levels and [³H]paroxetine binding and on the acute hyperthermic response. The acute hyperthermic response induced by MDMA (F(1,15)=48.09, P<0.001) was further increased by IL-1ß pretreatment (F(1,21)=13.48, P<0.01). Results shown as mean ± s.e.mean, n=4-13. Different from saline-treated rats: ^a,b,cP<0.05, 0.01, 0.001. Different from MDMA-treated
rats: P<0.05, 0.01.

Colado, M.I. et al., (1998) Br. J. Pharmacol. 124, 479-484.
Green, A.R. et al., (1995) Psychopharmacology 119, 246-260.
Grundy, R.I. et al., (1999) Brain Res., 830, 32-37.
Stroemer R.P. & Rothwell, N.J. (1998) J. Cereb. Blood Flow Metab. 18, 833-839.

M.I.C. thanks MCYT (SAF2001-1437) and FIS (02/1885) and E.O.S thanks UCM (PR1/03-11653) for financial support.