Role of the ERK signaling pathway in the actions of psychostimulants
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1
Karolinska Institutet, Department of Neuroscience, Faculty of Health,Medicine and Life Sciences, Sweden
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2
Institut François Magendie, INSERM U862, France
Psychostimulant-induced neuroplasticity in reward-related learning and memory processes is thought to involve long-lasting neural reorganization in part due to the distortion of dopamine-controlled striatal plasticity. Our recent work identified the extracellular signal-regulated kinase (ERK) as an important intracellular mediator of neuroplastic changes induced by these drugs. Cocaine and amphetamine increased ERK phosphorylation in a subset of neurons in reward-related brain regions including the dorsal and ventral striatum, the nucleus of the extended amygdala and deep layers of the limbic cortex. Using BAC transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter (drd1a-EGFP) or D2R promoter (drd2-EGFP), we have shown that ERK phosphorylation induced by psychostimulants is exclusively induced in striatonigral medium-size spiny neurons (MSNs) of the direct pathway. Genetic and pharmacological tools revealed that this activation involves a concomitant stimulation of D1 and glutamate NMDA receptors and requires the inhibition of protein phosphatase 1 (PP1) via dopamine- and cAMP-regulated phosphoprotein Mr 32, 000 (DARPP32). Pharmacological blockade of ERK activation impairs long-lasting behavioral changes, including psychomotor sensitization and conditioned place preference. Nuclear targets of ERK in MSNs include mitogen and stress-activated kinase 1 (MSK1) that will participate to the regulation of CREB and histone H3 phosphorylation. ERK also regulates directly or indirectly the transcription of immediate early genes, among which Krox24/Zif268 plays a critical role in behavioral plasticity. Altogether, these studies highlight the contribution of the ERK signaling pathway in the actions of psychostimulants and provide novel potential therapeutic approaches.
Conference:
3rd Mediterranean Conference of Neuroscience , Alexandria, Egypt, 13 Dec - 16 Dec, 2009.
Presentation Type:
Oral Presentation
Topic:
Symposium 07 – Cocaine and brain plasticity: new paths for treating addiction
Citation:
Valjent
E,
D
H,
A
GJ and
Oliet
S
(2009). Role of the ERK signaling pathway in the actions of psychostimulants.
Front. Neurosci.
Conference Abstract:
3rd Mediterranean Conference of Neuroscience .
doi: 10.3389/conf.neuro.01.2009.16.035
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Received:
19 Nov 2009;
Published Online:
19 Nov 2009.
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Correspondence:
Emmanuel Valjent, Karolinska Institutet, Department of Neuroscience, Faculty of Health,Medicine and Life Sciences, Stockholm, Sweden, nemoABS01@frontiersin.org