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

The ras-dependent protein kinase ERK pathway plays a role in the rewarding and locomotor effects of MDMA (ecstasy) in mice. Repeated MDMA treatment at 9 mg/kg (but not 3 or 6 mg/kg) induced conditioned place preference, a measure of reward, and increased locomotor activity; both effects were blocked by an inhibitor of ERK activation. MDMA also increased transcription of the immediate early gene c-fos in the caudate putamen, nucleus accumbens, and hippocampus, and of egr-1 and egr-3 in the caudate putamen. The ERK inhibitor suppressed these gene expression changes only in the caudate putamen, indicating that other signaling pathways regulate immediate early gene transcription elsewhere.

Study at a glance

Abstract

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. A significant CPP was observed after repeated MDMA treatment in CD‐1 mice at a dose of 9 mg kg −1 i.p. but not at 3 and 6 mg kg −1 . This rewarding effect was abolished by the selective inhibitor of ERK activation, SL327 (50 mg kg −1 ; i.p.). Similar results were obtained on MDMA‐induced locomotor activity, clearly suggesting a role of ERK pathway in these behavioral responses. 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. 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. British Journal of Pharmacology (2003) 140 , 831–838. doi: 10.1038/sj.bjp.0705506