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A Study on the Mechanisms by Which Minocycline Protects Against MDMA (‘Ecstasy’)-Induced Neurotoxicity of 5-HT Cortical Neurons

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Abstract

3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) is a selective 5-HT neurotoxin in rat brain which has been shown to produce acute neuroinflammation characterized by activation of microglia and release of interleukin-1beta (IL-1β). We aimed to determine whether or not minocycline, a semi-synthetic tetracycline antibiotic capable of inhibiting microglial activation, could prevent the inflammatory response and reduce the toxicity induced by MDMA. Adult male Dark Agouti rats were given minocycline twice a day for 2 days (45 mg/kg on the first day and 90 mg/kg on the second day; 12-h apart, i.p.). MDMA (12.5 mg/kg; i.p.) was given after the third minocycline injection and animals were killed either 1 h later for the determination of NFκB binding activity, 3 h later for the determination of IL-1β, 24 h later for the determination of microglial activation or 7 days later for the determination of [3H]-paroxetine binding as a measure of 5-HT neurotoxicity. MDMA increased NFκB activation, IL-1β release and microglial activation both in the frontal cortex and in the hypothalamus and 7 days later produced a reduction in the density of 5-HT uptake sites in both these brain areas. Minocycline prevented the MDMA-induced increase in NFκB activation, IL-1β release and microglial activation in the frontal cortex and prevented the 5-HT neurotoxicity 7 days later. However, in the hypothalamus, in spite of preventing MDMA-induced microglial activation, minocycline failed to prevent MDMA-induced NFκB activation, IL-1β release and neurotoxicity. This suggests that the protective mechanism of minocycline against MDMA-induced neurotoxicity in frontal cortex involves inhibition of MDMA-induced NFκB activation possibly through a reduction in IL-1β signalling.

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Abbreviations

IL-1β:

Interleukin-1β

MDMA:

3,4-Methylenedioxymethamphetamine

NFkB:

Nuclear factor kappaB

PBS:

Phosphate buffered saline

5-HIAA:

5-Hydroxyindole acetic acid

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Acknowledgements

We thank Dr. Paloma Martin-Sanz for assistance with the EMSA procedure. This study was supported by MCYT (Grant no. SAF2007-65175), Plan Nacional sobre Drogas (Grant no. PR75/06-15077), Ministerio de Sanidad (Grant no. RTA-RD06/0001/006), UCM-CAM (Grant no. CCG07-UCM/SAL-2588). The authors received predoctoral funding from Ministerio de Educación y Ciencia (LO,ET) and Comunidad de Madrid (MI, NL).

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  1. Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, 28040, Spain

    Laura Orio, Noemi Llopis, Elisa Torres, Maria Izco, Esther O’Shea & M. Isabel Colado

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  1. Laura Orio
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  2. Noemi Llopis
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  3. Elisa Torres
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  4. Maria Izco
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  5. Esther O’Shea
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Correspondence to M. Isabel Colado.

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Orio, L., Llopis, N., Torres, E. et al. A Study on the Mechanisms by Which Minocycline Protects Against MDMA (‘Ecstasy’)-Induced Neurotoxicity of 5-HT Cortical Neurons. Neurotox Res 18, 187–199 (2010). https://doi.org/10.1007/s12640-009-9120-3

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