Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum - PubMed (original) (raw)

. 2005 Jan 11;102(2):491-6.

doi: 10.1073/pnas.0408305102. Epub 2004 Dec 17.

Vincent Pascoli, Per Svenningsson, Surojit Paul, Hervé Enslen, Jean-Christophe Corvol, Alexandre Stipanovich, Jocelyne Caboche, Paul J Lombroso, Angus C Nairn, Paul Greengard, Denis Hervé, Jean-Antoine Girault

Affiliations

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

Emmanuel Valjent et al. Proc Natl Acad Sci U S A. 2005.

Abstract

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.

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Figures

Fig. 1.

Fig. 1.

_d_-amph-induced ERK activation in MSNs. (a) Double immunolabeling of P-ERK1/2 (red) and the indicated proteins (green) in the shell of the nucleus accumbens, 15 min after i.p. injection of _d_-amph (10 mg/kg) (see also Table 1). ChAT, choline acetyltransferase; Dyn, dynorphin; Enk, enkephalin. (b) Double immunolabeling of P-ERK (red) and phospho-Thr-34-DARPP-32 (P-DARPP-32, green) in vehicle-treated (Upper) or d-ampf-treated (Lower) mice. (c) Fifteen minutes before _d_-amph (+) or saline (-) injection, mice were treated with saline or MK801 (0.1 mg/kg). Neurons immunoreactive for P-DARPP-32 were counted, and the proportion of neurons immunoreactive for both P-DARPP-32 and P-ERK is indicated as filled bars. Virtually all P-ERK-positive neurons were P-DARPP-32-positive (not shown). Data are means ± SEM (neurons per shell field, five mice per group, _d_-amph-treated vs. control: *, P < 0.05; antagonist vs. saline pretreatment: º, P < 0.05). Photographs are single confocal sections. (Scale bars: 10 μm.)

Fig. 2.

Fig. 2.

Regulation of ERK and GluR1 phosphorylation in the mouse striatum in vivo by _d_-amph. Fifteen minutes after injection of saline (-)or _d_-amph (10 mg/kg) (+), phosphorylation of ERK2 and GluR1 at Ser-845 were quantified in the striatum by immunoblotting in mice pretreated with saline or the D1R antagonist SCH23390 (0.25 mg/kg, i.p.) 30 min before saline or _d_-amph (a), in wild-type (wt) or D1R knockout (D1R-KO) mice (b), or in mice pretreated with saline or the NMDAR antagonist MK801 (0.1 mg/kg) 30 min before saline or _d_-amph (c). Results are expressed as percentages of controls. Data are means ± SEM (five mice per group, _d_-amph-treated vs. control: *, P < 0.05; knockout vs. wild type or antagonist vs. saline pretreatment: º, P < 0.05).

Fig. 3.

Fig. 3.

Requirement of DARPP-32 in the activation of ERK in the striatum by drugs of abuse. (a) Immunoblot analysis (quantification in Right) of striatal extracts from wild-type (wt) and DARPP-32-knockout (KO) mice 15 min after i.p. injection of saline or _d_-amph (10 mg/kg). (b) Immunoblot analysis of prefrontal cortex extracts as in a. (c) Quantification of P-ERK-positive cells in sections of the nucleus accumbens from wt and DARPP-32-KO mice 10 min after injection of _d_-amph (10 mg/kg, i.p.) or cocaine (20 mg/kg, i.p.), or 20 min after injection of morphine (5 mg/kg, s.c.), nicotine (0.4 mg/kg, s.c.), or THC (1 mg/kg, i.p.), and their respective vehicle-treated controls. Data are means ± SEM (five mice per group, drug-treated vs. control: *, P < 0.05; KO vs. wt: º, P < 0.05).

Fig. 4.

Fig. 4.

DARPP-32 phosphorylation on residue Thr-34 is required for activation of ERK in the striatum by cocaine. (a) The number of P-ERK-positive neurons was quantified in dorsal striatum (DStr), nucleus accumbens (shell and core), and prefrontal cortex (Pfx) in wild-type (wt) and Thr-34 → Ala DARPP-32 (T34A) mutant mice 10 min after i.p. injection of saline or cocaine (20 mg/kg). (b) Same experiment in wild-type and Thr-75 → Ala DARPP-32 (T75A) mutant mice. (c) Phosphorylation of transcription factor Elk-1 Ser-383 was examined in wild-type and Thr-34 → Ala DARPP-32 (T34A) mutant mice 10 min after i.p. injection of saline or cocaine (20 mg/kg). The number of immunofluorescent neuronal nuclei labeled with phosphorylation state-specific antibodies was quantified in dorsal striatum (DStr), nucleus accumbens (shell and core), and prefrontal cortex (Pfx). Data are means ± SEM; six mice per group; treated vs. control: *, P < 0.01; wild type vs. mutant: º, P < 0.05.

Fig. 5.

Fig. 5.

Role of DARPP-32 and ERK activation in behavioral sensitization. (a) Locomotor activity was measured in response to a first injection (1st inj) of cocaine (20 mg/kg, i.p.) in mice pretreated with vehicle (open bars) or SL327 (30 mg/kg i.p., filled bars), 30 min before cocaine injection. Locomotor activity in response to vehicle injection did not differ between saline-pretreated (145 ± 68¼ turns per 60 min) and SL327-pretreated (119 ± 27¼ turns per 60 min) mice. The response to a test injection of cocaine (Test inj) was measured either 2 days (2d) or 7 days (7d) later. (b) The locomotor effects of the first and test injections of cocaine were examined by using the same protocol in wild-type (wt) and Thr-34 → Ala DARPP-32 (T34A) mutant mice (11 mice per group). *, P < 0.01 test vs. first injection; º, P < 0.01 SL327 vs. saline pretreatment, or mutant vs. wild type.

Fig. 6.

Fig. 6.

Requirement of DARPP-32 in _d_-amph-induced phosphorylation of STEP and MEK. (a) Regulation of STEP phosphorylation in striatum from wild-type (wt) and DARPP-32-knockout (KO) mice injected with saline or _d_-amph (10 mg/kg, i.p.). Phosphorylation of STEP (P-STEP) is indicated by the upward shift of the 46-kDa isoform (STEP46). STEP46 phosphorylation was expressed as the ratio P-STEP46/total STEP46. (b) Regulation of MEK phosphorylation in striatum from wt and KO mice injected with saline or _d_-amph (10 mg/kg, i.p.). MEK phosphorylation was expressed as percentage of controls. Data are means ± SEM (six mice per group; treated vs. control: *, P < 0.01; treated KO mice vs. wt: º, P < 0.05). (c) Schematic representation of the role of phosphatase regulation in the stimulation of ERK after activation of D1R and NMDAR by acute psychostimulant administration.

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