ABSTRACT
Title
3,4-methylenedioxymethamphetamine (MDMA) regulates opioid gene expression in the rat brainstem through the involvement of serotonin and the activation of CREB and ERK cascade
Authors
M. Di Benedetto1, S. del C. Bastías Candia1, C. D’Addario1, S. Candeletti1 and P. Romualdi1
Dept. of Pharmacology, Irnerio 48, 40126 Bologna
Dept. of Pharmacology, Irnerio 48, 40126 Bologna
Abstract
3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy), a widely used recreational drug causes complex adaptations at the molecular and cellular levels altering the activity of different brain neurotransmitters (Rudnick and Wall 1992; Gudelsky and Nash 1996; Colado et al. 2004). Here we aimed to verify the effects of single and repeated injections of MDMA on dynorphin and nociceptin systems gene regulation in the brainstem, which include the dorsal raphe nucleus, where the cell bodies of serotonin (5-HT) neurons are located. Both acute and chronic (twice a day for 7 days) MDMA (8 mg/kg) elicited 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/NOP system gene 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. We have also been able to establish a causal relationship between increased P-ERK levels and prodynorphin mRNA by the pharmacological blockade of ERK phosphorylation achieved with PD98059 on prodynorphin gene expression.
In conclusion our data suggest the involvement of dynorphin in the effects evoked by MDMA in the brainstem, possibly via CREB and ERK1/2 cascade activation, probably through serotoninergic mechanisms, at least acutely. Chronically, it is also possible to hypothesize a general inhibitor role of 5-HT in the effects evoked by MDMA. Moreover, these findings strengthen the hypothesis, already proposed (Mabuchi et al. 2001), of a neuroprotective role for both CREB and dynorphin.
Rudnick and Wall (1992) Proc Natl Acad Sci USA 89, 1817–1821
Gudelsky and Nash (1996) J Neurochem 66, 243–249
Colado et al (2004) Psychopharmacol (Berl) 173, 249–263
Mabuchi et al (2001) J Neurosci 21, 9204–9213
In conclusion our data suggest the involvement of dynorphin in the effects evoked by MDMA in the brainstem, possibly via CREB and ERK1/2 cascade activation, probably through serotoninergic mechanisms, at least acutely. Chronically, it is also possible to hypothesize a general inhibitor role of 5-HT in the effects evoked by MDMA. Moreover, these findings strengthen the hypothesis, already proposed (Mabuchi et al. 2001), of a neuroprotective role for both CREB and dynorphin.
Rudnick and Wall (1992) Proc Natl Acad Sci USA 89, 1817–1821
Gudelsky and Nash (1996) J Neurochem 66, 243–249
Colado et al (2004) Psychopharmacol (Berl) 173, 249–263
Mabuchi et al (2001) J Neurosci 21, 9204–9213