Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum

被引:487
作者
Valjent, E
Pascoli, V
Svenningsson, P
Paul, S
Enslen, H
Corvol, JC
Stipanovich, A
Caboche, J
Lombroso, PJ
Nairn, AC
Greengard, P
Hervé, D
Girault, JA
机构
[1] Univ Paris 06, U536, Inst Fer Moulin, F-75005 Paris, France
[2] Inst Natl Sante & Rech Med, F-75005 Paris, France
[3] Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA
[4] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA
[5] Univ Paris 06, CNRS, UMR 7102, Lab Signalisat Neuronale & Regulat Gen, F-75005 Paris, France
[6] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06508 USA
关键词
dopamine D1 receptor; drug addiction; NMDA receptor; nucleus accumbens; protein kinase;
D O I
10.1073/pnas.0408305102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Many drugs of abuse exert their addictive effects by increasing extracellular dopamine in the nucleus accumbens, where they likely alter the plasticity of corticostriatal glutamatergic transmission. This mechanism implies key molecular alterations in neurons in which both dopamine and glutamate inputs are activated. Extracellular signal-regulated kinase (ERK), an enzyme important for long-term synaptic plasticity, is a good candidate for playing such a role. Here, we show in mouse that d-amphetamine activates ERK in a subset of medium-size spiny neurons of the dorsal striatum and nucleus accumbens, through the combined action of glutamate NMDA and D1-dopamine receptors. Activation of ERK by d-amphetamine or by widely abused drugs, including cocaine, nicotine, morphine, and Delta(9)-tetrahydrocannabinol was absent in mice lacking dopamine- and cAMP-regulated phosphoprotein of M-r 32,000 (DARPP-32). The effects of d-amphetamine or cocaine on ERK activation in the striatum, but not in the prefrontal cortex, were prevented by point mutation of Thr-34, a DARPP-32 residue specifically involved in protein phosphatase-1 inhibition. Regulation by DARPP-32 occurred both upstream of ERK and at the level of striatal-enriched tyrosine phosphatase (STEP). Blockade of the ERK pathway or mutation of DARPP-32 altered locomotor sensitization induced by a single injection of psychostimulants, demonstrating the functional relevance of this regulation. Thus, activation of ERK, by a multilevel protein phosphatase-controlled mechanism, functions as a detector of coincidence of dopamine and glutamate signals converging on medium-size striatal neurons and is critical for long-lasting effects of drugs of abuse.
引用
收藏
页码:491 / 496
页数:6
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