Role of the ERK pathway in psychostimulant-induced locomotor sensitization

BACKGROUND: Repeated exposure to psychostimulants results in a progressive and long-lasting facilitation of the locomotor response that is thought to have implications for addiction. Psychostimulants and other drugs of abuse activate in specific brain areas extracellular signal-regulated kinase (ERK), an essential component of a signaling pathway involved in synaptic plasticity and long-term effects of drugs of abuse. Here we have investigated the role of ERK activation in the behavioral sensitization induced by repeated administration of psychostimulants in mice, using SL327, a brain-penetrating selective inhibitor of MAP-kinase/ERK kinase (MEK), the enzyme that selectively activates ERK. RESULTS: A dose of SL327 (30 mg/kg) that reduced the number of activated ERK-positive neurons by 62 to 89% in various brain areas, had virtually no effect on the spontaneous locomotor activity or the acute hyperlocomotion induced by cocaine or D-amphetamine. Pre-treatment with SL327 (30 mg/kg) prior to each drug administration prevented the locomotor sensitization induced by repeated injections of D-amphetamine or cocaine. The SL327 pre-treatment abolished also conditioned locomotor response of mice placed in the context previously paired with cocaine or D-amphetamine. In contrast, SL327 did not alter the expression of sensitized response to D-amphetamine or cocaine. CONCLUSION: Altogether these results show that ERK has a minor contribution to the acute locomotor effects of psychostimulants or to the expression of sensitized responses, whereas it is crucial for the acquisition of locomotor sensitization and psychostimulant-conditioned locomotor response. This study supports the important role of the ERK pathway in long-lasting behavioral alterations induced by drugs of abuse

Convulsant Doses of a Dopamine D1 Receptor Agonist Result in Erk-Dependent Increases in Zif268 and Arc/Arg3.1 Expression in Mouse Dentate Gyrus

Activation of dopamine D1 receptors (D1Rs) has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings in the dentate gyrus revealed the presence of epileptiform discharges peaking at 30–45 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2 (ERK), in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory

A phosphatase cascade by which rewarding stimuli control nucleosomal response

ArticleInternational audienceDopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascad

The Tail of the Striatum: From Anatomy to Connectivity and Function

International audienceThe dorsal striatum, the largest subcortical structure of the basal ganglia, is critical in controlling motor, procedural, and reinforcement-based behaviors. Although in mammals the striatum extends widely along the rostro-caudal axis, current knowledge and derived theories about its anatomo-functional organization largely rely on results obtained from studies of its rostral sectors, leading to potentially oversimplified working models of the striatum as a whole. Recent findings indicate that the extreme caudal part of the striatum, also referred to as the tail of striatum (TS), represents an additional functional domain. Here, we provide an overview of past and recent studies revealing that the TS displays a heterogeneous cell-type-specific organization, and a unique input-output connectivity, which poises the TS as an integrator of sensory processing

LA VOIE MAPK/ERK (UN SUBSTRAT NEUROBIOLOGIQUE DE LA DEPENDANCE AUX SUBSTANCES TOXICOMANOGENES)

LE BUT DE CE TRAVAIL FUT DE VALIDER UN MODELE PERMETTANT L'ETUDE DES PROPRIETES MOTIVATIONNELLES INDUITES PAR LE THC CHEZ LA SOURIS PUIS D'EVALUER LE ROLE DE LA VOIE DE SIGNALISATION MAPK/ERK DANS LA MISE EN PLACE DES ADAPTATIONS NEURONALES RESPONSABLES DES COMPORTEMENTS ADDICTIFS DU THC ET DE LA COCAINE. LES REPONSES MOTIVATIONNELLES INDUITES PAR LE THC ONT ETE EVALUEES DANS LE TEST DE PREFERENCE DE PLACE, EN MINIMISANT LES EFFETS DYSPHORIQUES INDUITS PAR LA PREMIERE EXPOSITION A LA DROGUE ET/OU LES CONSEQUENCES DES PROPRIETES PHARMACOCINETIQUES DU COMPOSE. AINSI, SELON LA DOSE ET LE PROTOCOLE EXPERIMENTAL UTILISE, LE THC EST CAPABLE D'INDUIRE A LA FOIS DES EFFETS RENFORCANTS ET AVERSIFS. L'ADMINISTRATION AIGUE DE COCAINE ET DE THC CHEZ LA SOURIS, S'ACCOMPAGNE D'UNE AUGMENTATION TRANSITOIRE DE LA PHOSPHORYLATION DES ERKS DANS LES CELLULES STRIATALES. LA LIBERATION DE DOPAMINE CONSTITUE UN EVENEMENT MAJEUR DANS L'ACTIVATION DES ERKS QUI EST TOTALEMENT DEPENDANTE DE LA STIMULATION DES RECEPTEURS D1 AVEC UNE CONTRIBUTION PARTIELLE DES RECEPTEURS D2. LES RECEPTEURS NMDA INTERVIENNENT EGALEMENT DANS L'ACTIVATION DES ERKS PAR CES DEUX SUBSTANCES. L'ACTIVATION DU FACTEUR DE TRANSCRIPTION ELK-1 ET LA REGULATION TRANSCRIPTIONNELLE DES GENES PRECOCES C-FOS ET ZIF268 EN REPONSE A L'ADMINISTRATION AIGUE DE THC ET DE COCAINE SONT CONTROLEES PAR LES VOIES ERKS. ENFIN, LE BLOCAGE DES VOIES ERKS PAR UN INHIBITEUR DE MEK (SL327) ABOLIT LA PREFERENCE DE PLACE CONDITIONNEE INDUITE PAR LA COCAINE ET LE THC AINSI QUE LA SENSIBILISATION LOCOMOTRICE INDUITE PAR UNE ADMINISTRATION REPETEE DE COCAINE SANS TOUTEFOIS AFFECTER LES REPONSES COMPORTEMENTALES AIGUES INDUITES PAR CES DEUX DROGUES. L'ACTIVATION DES ERKS DANS LES CELLULES STRIATALES CONSTITUERAIT UN MECANISME COMMUN D'ACTION DE CES DROGUES. EN CONTROLANT UNE PREMIERE VAGUE DE REGULATIONS GENIQUES, CETTE VOIE DE TRANSDUCTION JOUERAIT UN ROLE MAJEUR DANS LES ADAPTATIONS NEURONALES RESPONSABLES DES COMPORTEMENTS ADDICTIFS A LONG TERME.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Ribosomal Protein S6 Phosphorylation in the Nervous System: From Regulation to Function

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Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Induced Gene Regulation in Brain

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