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 ⌬ 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.dopamine D1 receptor ͉ drug addiction ͉ NMDA receptor ͉ nucleus accumbens ͉ protein kinase M any drugs of abuse share the ability to stimulate dopamine transmission in the nucleus accumbens (1). They are thought to mimic the effects of naturally reinforcing stimuli and divert the normal role of dopamine neurons in coding reward prediction errors (2). Dopamine modulates long-term depression and potentiation at glutamatergic corticostriatal synapses, and current models of striatal circuits suggest that the regulation of the plasticity of corticostriatal transmission is a central mechanism of dopamine-controlled-learning (3, 4). One prediction of these models is that key biochemical events should occur specifically in neurons in which both dopamine and glutamate inputs are activated. Activation of extracellular signal-regulated kinase (ERK) is a candidate for such a role because it depends on both dopamine and glutamate receptors (5). In addition, ERK activity is known to be important for long-term synaptic plasticity (6), and its pharmacological blockade prevents the transcriptional and rewarding effects of cocaine and ⌬ 9 -tetrahydrocannabinol (THC) (5, 7). To determine the role of ERK in the long-term action of dopamine in the striatum, it is critical to identify in which neurons it is activated and the mechanism of this activation. In ...

Psychostimulants and other drugs of abuse activate extracellular signal-regulated kinase (ERK) in the striatum, through combined stimulation of dopamine D 1 receptors (D1Rs) and glutamate NMDA receptors. Antipsychotic drugs activate similar signaling proteins in the striatum by blocking dopamine D 2 receptors (D2Rs). However, the neurons in which these pathways are activated by psychotropic drugs are not precisely identified. We used transgenic mice, in which enhanced green fluorescent protein (EGFP) expression was driven by D1R promoter (drd1a-EGFP) or D2R promoter (drd2-EGFP). We confirmed the expression of drd1a-EGFP in striatonigral and drd2-EGFP in striatopallidal neurons. Drd2-EGFP was also expressed in cholinergic interneurons, whereas no expression of either promoter was detected in GABAergic interneurons. Acute cocaine treatment increased phosphorylation of ERK and its direct or indirect nuclear targets, mitogen-and stress-activated kinase-1 (MSK1) and histone H3, exclusively in D1R-expressing output neurons in the dorsal striatum and nucleus accumbens. Cocaine-induced expression of c-Fos and Zif268 predominated in D1R-expressing neurons but was also observed in D2R-expressing neurons. One week after repeated cocaine administration, cocaine-induced signaling responses were decreased, with the exception of enhanced ERK phosphorylation in dorsal striatum. The responses remained confined to D1R neurons. In contrast, acute haloperidol injection activated phosphorylation of ERK, MSK1, and H3 only in D2R neurons and induced c-fos and zif268 predominantly in these neurons. Our results demonstrate that cocaine and haloperidol specifically activate signaling pathways in two completely segregated populations of striatal output neurons, providing direct evidence for the selective mechanisms by which these drugs exert their long-term effects.

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A major goal of research on addiction is to identify the molecular mechanisms of long-lasting behavioural alterations induced by drugs of abuse. Cocaine and delta-9-tetrahydrocannabinol (THC) activate extracellular signal-regulated kinase (ERK) in the striatum and blockade of the ERK pathway prevents establishment of conditioned place preference to these drugs. However, it is not known whether activation of ERK in the striatum is specific for these two drugs and/or this brain region. We studied the appearance of phospho-ERK immunoreactive neurons in CD-1 mouse brain following acute administration of drugs commonly abused by humans, cocaine, morphine, nicotine and THC, or of other psychoactive compounds including caffeine, scopolamine, antidepressants and antipsychotics. Each drug generated a distinct regional pattern of ERK activation. All drugs of abuse increased ERK phosphorylation in nucleus accumbens, lateral bed nucleus of the stria terminalis, central amygdala and deep layers of prefrontal cortex, through a dopamine D1 receptor-dependent mechanism. Although some non-addictive drugs moderately activated ERK in a few of these areas, they never induced this combined pattern of strong activation. Antidepressants and caffeine activated ERK in hippocampus and cerebral cortex. Typical antipsychotics mildly activated ERK in dorsal striatum and superficial prefrontal cortex, whereas clozapine had no effect in the striatum, but more widespread effects in cortex and amygdala. Our results outline a subset of structures in which ERK activation might specifically contribute to the long-term effects of drugs of abuse, and suggest mapping ERK activation in brain as a way to identify potential sites of action of psychoactive drugs.

Drug addiction results in part from the distortion of dopamine-controlled plasticity, and extracellular signal-regulated kinase (ERK) plays an important role in the underlying molecular mechanisms of this process. ERK is activated by drugs of abuse in a subset of neurons in reward-related brain regions. This activation, necessary for the expression of immediate early genes, depends upon dopamine D1 and glutamate receptors. Blockade of ERK activation prevents long-lasting behavioral changes, including psychomotor sensitization and conditioned place preference. It also interferes with drug craving and drug-associated memory reconsolidation. By contrast, ERK1 mutation enhances the effects of morphine and cocaine. We suggest that the ERK2 pathway acts as a logical AND gate, permissive for plasticity, in neurons on which dopamine-mediated reward signals and glutamate-mediated contextual information converge.

, demonstrating the existence of drug-induced chromatin remodeling in vivo. In MSK1 knock-out (KO) mice CREB and H3 phosphorylation in response to cocaine (10 mg/kg) were blocked, and induction of c-Fos and dynorphin was prevented, whereas the induction of Egr-1 (early growth response-1)/zif268/Krox24 was unaltered. MSK1-KO mice had no obvious neurological defect but displayed a contrasted behavioral phenotype in response to cocaine. Acute effects of cocaine and dopamine D 1 or D 2 agonists were unaltered. Sensitivity to low doses, but not high doses, of cocaine was increased in the conditioned place preference paradigm, whereas locomotor sensitization to repeated injections of cocaine was decreased markedly. Our results show that MSK1 is a major striatal kinase, downstream from ERK, responsible for the phosphorylation of CREB and H3 and is required specifically for the induction of c-Fos and dynorphin as well as for locomotor sensitization.

Repeated association of drugs of abuse with context leads to long-lasting behavioral responses that reflect reward-controlled learning and participate in the establishment of addiction. Reactivation of consolidated memories is known to produce a reconsolidation process during which memories undergo a labile state. We investigated whether reexposure to drugs had similar effects. Cocaine administration activates extracellular signal-regulated kinase (ERK) in the striatum, and ERK activation is required for the acquisition of cocaine-induced conditioned place preference (CPP). When mice previously conditioned for cocaine-place preference were reexposed to cocaine in the drug-paired compartment after systemic administration of SL327, an inhibitor of ERK activation, CPP response was abolished 24 h later. This procedure also abolished the phosphorylation of ERK and glutamate receptor-1 observed in the ventral and dorsal striatum, 24 h later, during CPP test. Erasure of CPP by SL327 required the combination of cocaine administration and drug-paired context and did not result from enhanced extinction. Similarly, reexposure to morphine in the presence of SL327 long-lastingly abolished response of previously learned morphine-CPP. The effects of SL327 on cocaine-or morphine-CPP were reproduced by protein synthesis inhibition. In contrast, protein synthesis inhibition did not alter previously acquired locomotor sensitization to cocaine. Our findings show that an established CPP can be disrupted when reactivation associates both the conditioned context and drug administration. This process involves ERK, and systemic treatment preventing ERK activation during reexposure erases the previously learned behavioral response. These results suggest potential therapeutic strategies to explore in the context of addiction.cocaine ͉ locomotor sensitization ͉ morphine ͉ protein kinase inhibitor ͉ reconsolidation A ddiction to licit or illicit drugs is a major public health issue worldwide. This behavioral disease results from a combination of environmental and genetic factors that are the focus of intense research. One important property of drugs of abuse is their common ability to increase extracellular dopamine (DA) in the nucleus accumbens (NAcc) (1). They are thought to mimic and divert thereby a physiological learning mechanism that results from the ability of DA neurons to code for errors in reward prediction (2). In support of this model, electrophysiological studies indicate that DA controls the flow of information through the striatum as well as the plasticity of corticostriatal synapses and plays a critical role in the acquisition and expression of drug-related behaviors (3, 4).Some molecular mechanisms underlying long-lasting behavioral alterations produced by drugs of abuse have been identified (see refs. 5 and 6 for reviews). Recently, the role of extracellular signal-regulated kinase (ERK) 1 and 2, and more specifically ERK2, an intracellular pathway activated by most drugs of abuse, has attracted much attention (7-10). In ...

Dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures1,2. Its molecular pathophysiology is poorly understood, in part due to limited knowledge of the genetic basis of the disorder. Only three genes for primary torsion dystonia (PTD), TOR1A (DYT1)3, THAP1 (DYT6)4, and CIZ15 have been identified. Using exome sequencing in two PTD families we identified a novel causative gene, GNAL, with a nonsense p.S293X mutation resulting in premature stop codon in one family and a missense p.V137M mutation in the other. Screening of GNAL in 39 PTD families, revealed six additional novel mutations in this gene. Impaired function of several of the mutations was shown by bioluminescence resonance energy transfer (BRET) assays.