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Regulation of opioid gene expression in the rat brainstem by 3,4-methylenedioxymethamphetamine (MDMA): role of serotonin and involvement of CREB and ERK cascade

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Abstract

The amphetamine analogue 3,4-methylendioxymetamphetamine (MDMA, Ecstasy) causes complex adaptations at the molecular and cellular levels altering the activity of different brain neurotransmitters. The present study aims to verify the effects of single and repeated injections of MDMA on dynorphin and nociceptin systems gene regulation in the brainstem, an area rich in neurons containing serotonin. Both acute and chronic (twice a day for 7 days) MDMA (8 mg/kg) induced a marked increase in prodynorphin mRNA levels as well as in cAMP response element-binding protein (CREB) and extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation, without causing any effect on kappa opioid receptor or nociceptin system (both pronociceptin and its receptor) genes expression, in this brain region. The blockade of 5HT1/5HT2 receptors by methysergide abolished the acute MDMA-induced increase in prodynorphin. Moreover, the concomitant chronic administration of both methysergide and MDMA (7 days) induced a significant increase in all the dynorphin or nociceptin system genes expression and in CREB and ERK phosphorylation. Our data suggest the involvement of dynorphin in the effects evoked by MDMA in the brainstem, possibly via CREB and ERK1/2 cascade activation, since the ERK inhibitor PD98059 prevented the MDMA-induced prodynorphin gene expression, and, acutely, also through the involvement of serotoninergic mechanisms. Chronically, it is also possible to hypothesize a general inhibitor role of serotonin in the effects evoked by MDMA. Moreover, these findings strengthen the hypothesis, already proposed, of a neuroprotective role for both CREB and dynorphin.

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Acknowledgements

This work was supported by grants from the University of Bologna RFO08 (to PR). We wish to thank the National Institute on Drug Abuse/National Institute of Health, USA, for providing MDMA for experimental use (Research Triangle Park).

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Authors and Affiliations

  1. Department of Pharmacology, Alma Mater Studiorum-University of Bologna, via Irnerio 48, 40126, Bologna, Italy

    Manuela Di Benedetto, Sussy del Carmen Bastías Candia, Claudio D’Addario, Elena Elettra Porticella, Chiara Cavina, Sanzio Candeletti & Patrizia Romualdi

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  1. Manuela Di Benedetto
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  2. Sussy del Carmen Bastías Candia
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  3. Claudio D’Addario
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  4. Elena Elettra Porticella
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  7. Patrizia Romualdi
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Correspondence to Manuela Di Benedetto.

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Manuela Di Benedetto and Sussy del Carmen Bastías Candia equally contributed to this paper.

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Di Benedetto, M., Bastías Candia, S., D’Addario, C. et al. Regulation of opioid gene expression in the rat brainstem by 3,4-methylenedioxymethamphetamine (MDMA): role of serotonin and involvement of CREB and ERK cascade. Naunyn-Schmied Arch Pharmacol 383, 169–178 (2011). https://doi.org/10.1007/s00210-010-0587-5

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