Importance of ERK activation in behavioral and biochemical effects induced by MDMA in mice

Abstract

1 Little is known about the cellular effects induced by 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), although changes in gene expression have been observed following treatments with other psychostimulants. Thus, the aim of this study was to investigate in mice, the relationships between the ras-dependent protein kinase ERK and MDMA-induced reinforcement using the conditioned place preference (CPP) and locomotor activity measurements. This was completed using real-time quantitative PCR method by a study of immediate early-genes (IEGs) transcription known to be involved in neuronal plasticity. 2 A significant CPP was observed after repeated MDMA treatment in CD-1 mice at a dose of 9 mg kg À1 i.p. but not at 3 and 6 mg kg À1 . This rewarding effect was abolished by the selective inhibitor of ERK activation, SL327 (50 mg kg À1 ; i.p.). Similar results were obtained on MDMA-induced locomotor activity, clearly suggesting a role of ERK pathway in these behavioral responses.3 Following acute i.p. injection, MDMA induced a strong c-fos transcription in brain structures, such as caudate putamen, nucleus accumbens and hippocampus, whereas egr-1 and egr-3 transcripts were only increased in the caudate putamen. MDMA-induced IEGs transcription was selectively suppressed by SL327 in the caudate putamen, suggesting a role for other signaling pathways in regulation of IEGs transcription in the other brain structures. In agreement with these results, MDMA-induced c-fos protein expression was blocked by SL327 in the caudate putamen. 4 This study confirms and extends to mice the reported role of ERK pathway in the development of addiction-like properties of MDMA. This could facilitate studies about the molecular mechanism of this process by using mutant mice.

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

“…A trend for slightly higher levels of ERK1/2 phosphorylation in GKO mice (WT-Mor vs KO-Mor: F(3, 19) ¼ 2.4; p ¼ 0.08) correlates with the tendency for these animals to show increased behavioral sensitivity to morphine. Together with studies showing that ERK activity is necessary for place preference (Girault et al, 2007;Salzmann et al, 2003;Valjent et al, 2001Valjent et al, , 2006aValjent et al, , b, 2004 and that galanin reduces morphine CPP (Zachariou et al, 1999), these data suggest that galanin might regulate morphine reward via regulation of ERK signaling in the VTA. It is also possible that ERK activity in the VTA regulates the ability of galanin to modulate morphineinduced locomotor activation.…”

Perspectives on Zebrafish Models of Hallucinogenic Drugs and Related Psychotropic Compounds

“…As shown in Table 2, selected hallucinogens drugs affect both c-fos and cortisol levels in adult zebrafish. Notably, altered c-fos brain expression and cortisol/corticosterone levels have been reported in various mammalian models following hallucinogenic drugs, including LSD, 163,164 MDMA, 165,166 ketamine, 167,168 and PCP. 113,169 Zebrafish display a welldeveloped neuroendocrine system 74,170 and show high sensitivity of their CNS proto-oncogene expression to various experimental manipulations.…”

Knockout of ERK1 Enhances Cocaine-Evoked Immediate Early Gene Expression and Behavioral Plasticity

“…Pharmacological blockade of the Raf-MEK-ERK cascade also attenuates the development of a conditioned place preference to cocaine, amphetamine or MDMA (Valjent et al, 2000;Salzmann et al, 2003;Gerdjikov et al, 2004) and appears to modulate the development of psychomotor sensitization to cocaine (Pierce et al, 1999;Valjent et al, 2005). In addition, administration of psychomotor stimulant drugs increases ERK activity in several mesocorticolimbic brain regions associated with drug addiction (Valjent et al, 2000(Valjent et al, , 2005Adams et al, 2001; and the induction of immediate early genes (IEGs) in these brain regions is largely attenuated by pharmacological blockade of this pathway (Valjent et al, 2000;Salzmann et al, 2003;Ferguson and Robinson, 2004).…”