Regulation of opioid gene expression in the rat brainstem by 3,4-methylenedioxymethamphetamine (MDMA): role of serotonin and involvement of CREB and ERK cascade.
Manuela Di Benedetto, Sussy del Carmen Bastías Candia, Claudio D'Addario, Elena Elettra Porticella, Chiara Cavina, Sanzio Candeletti, Patrizia Romualdi
Naunyn-Schmiedeberg's Archives of Pharmacology February 2011 DOI: 10.1007/s00210-010-0587-5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Rats (brainstem tissue) |
| Interventions | MDMA Methysergide PD98059 |
| Dose | 8 mg/kg MDMA |
| Duration | Acute and 7 days (twice a day for chronic) |
| Measures | prodynorphin mRNA levels, CREB phosphorylation, ERK1/2 phosphorylation, kappa opioid receptor gene expression, pronociceptin gene expression, nociceptin receptor gene expression |
| Topics | MDMA Serotonin |
| Key findings | MDMA (8 mg/kg) increased prodynorphin mRNA and CREB/ERK1/2 phosphorylation in the brainstem after acute and chronic administration, without affecting kappa opioid receptor or nociceptin system genes. Methysergide blocked the acute effect, while chronic co-administration increased all dynorphin and nociceptin genes. ERK inhibition prevented prodynorphin induction, suggesting a role for the ERK/CREB pathway. |
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.
Comparable studies
Other preclinical and animal studies on MDMA, most cited first.
Citations in the library
Cited by 4
- Sex-Dependent Psychoneuroendocrine Effects of THC and MDMA in an Animal Model of Adolescent Drug Consumption PLoS One November 4, 2013
- Discriminative Stimulus Effects of Hallucinogenic Drugs: a Possible Relation to Reinforcing and Aversive Effects Journal of Pharmacological Sciences June 12, 2019
- The Discriminative Stimulus Properties of Hallucinogenic and Dissociative Anesthetic Drugs. Current Topics in Behavioral Neurosciences 2018
- Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure. Pharmacological Research December 2016
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and 4 more in the library