Sci. STKE, 18 January 2005
ADDICTION A DARPP Side to ERK
Drug addiction is associated with changes in neuronal function that can be considered a form of learning. Many drugs of abuse enhance dopaminergic neurotransmission in the nucleus accumbens and are thereby thought to influence the plasticity of glutamatergic corticostriatal neurons (suggesting effects on neurons that receive both dopaminergic and glutamatergic input). Valjent et al. uncovered converging effects of dopaminergic and glutamatergic signals in response to drugs of abuse that led to activation of extracellular signal-regulated kinase (ERK, a target of dopaminergic and glutamatergic activity that has been implicated in synaptic plasticity) in striatal neurons. D-amphetamine injection stimulated ERK phosphorylation in a subset of mouse dopamine D1 receptor (D1R)-bearing neurons in dorsal striatum and nucleus accumbens. D-amphetamine also stimulated phosphorylation of the D1R targets dopamine and cAMP-regulated phosphoprotein of Mr 32,000 (DARPP-32) and the glutamate receptor 1 subunit (GluR1). Phosphorylation of ERK and GluR1 in response to d-amphetamine was inhibited by D1R blockade or knockout, whereas pharmacological blockade of the glutamatergic N methyl-D-aspartate receptor inhibited ERK phosphorylation but not that of GluR1 or DARPP-32. DARPP-32 knockout attenuated striatal ERK phosphorylation in response to d-amphetamine or other drugs of abuse. Further, mutation of a DARPP-32 threonine residue implicated in its inhibition of protein phosphatase-1 (Thr-34) abolished cocaine or d-amphetamine-mediated phosphorylation of striatal ERK and of the ERK substrate Elk-1 but did not affect ERK activation in the prefrontal cortex. DARPP-32 knockout, Thr-34 mutation, or pharmacological blockade of the ERK signaling pathway also inhibited behavioral sensitization to cocaine. DARPP-32 both promoted ERK phosphorylation and inhibited ERK dephosphorylation. Gould and Manji provide context and discuss implications of this research in a Commentary.
E. Valjent, V. Pascoli, P. Svenningsson, S. Paul, H. Enslen, J.-C. Corvol, A. Stipanovich, J. Caboche, P. J. Lombroso, A. C. Nairn, P. Greengard, D. Hervé, J.-A. Girault, Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl. Acad. Sci. U.S.A. 102, 491-496 (2005). [Abstract] [Full Text]
T. D. Gould, H. K. Manji, DARPP-32: A molecular switch at the nexus of reward pathway plasticity. Proc. Natl. Acad. Sci. U.S.A. 102, 253-254 (2005). [Full Text]
Citation: A DARPP Side to ERK. Sci. STKE 2005, tw23 (2005).
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