title: Regulation of opioid gene expression in the rat brainstem by 3,4-methylenedioxymethamphetamine (MDMA): role of serotonin and involvement of CREB and ERK cascade.
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.
authors.affiliation: Department of Pharmacology, Alma Mater Studiorum-University of Bologna, via Irnerio 48, 40126, Bologna, Italy. manuela.dibenedetto@unibo.it
authors.forename: Manuela
authors.initials: M
authors.lastname: Di Benedetto
authors.forename: Sussy del Carmen
authors.initials: Sdel C
authors.lastname: Bastías Candia
authors.forename: Claudio
authors.initials: C
authors.lastname: D'Addario
authors.forename: Elena Elettra
authors.initials: EE
authors.lastname: Porticella
authors.forename: Chiara
authors.initials: C
authors.lastname: Cavina
authors.forename: Sanzio
authors.initials: S
authors.lastname: Candeletti
authors.forename: Patrizia
authors.initials: P
authors.lastname: Romualdi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001933:Brain Stem / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D018847:Opioid Peptides / Q000235:genetics*; D010766:Phosphorylation; D011498:Protein Precursors / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000235:genetics; D044263:Receptors, Serotonin, 5-HT1 / Q000378:metabolism; D044348:Receptors, Serotonin, 5-HT2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction; D000097629:Nociceptin
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D004745:Enkephalins; D048049:Extracellular Signal-Regulated MAP Kinases; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D018847:Opioid Peptides; D011498:Protein Precursors; D017473:Receptors, Opioid, kappa; D044263:Receptors, Serotonin, 5-HT1; D044348:Receptors, Serotonin, 5-HT2; D012701:Serotonin; D012702:Serotonin Antagonists; D000097629:Nociceptin; C033660:preproenkephalin