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Assessment of Cocaine-induced Behavioral Sensitization and Conditioned Place Preference in Mice
Published on: February 18, 2016
Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice
Karen Brami-Cherrier1, Emmanuel Valjent, Denis Hervé
1Centre National de la Recherche Scientifique, Université Pierre et Marie Curie, Unité Mixte de Recherche 7102, 75005 Paris, France.
Abstract:
Although the induction of persistent behavioral alterations by drugs of abuse requires the regulation of gene transcription, the precise intracellular signaling pathways that are involved remain mainly unknown. Extracellular signal-regulated kinase (ERK) is critical for the expression of immediate-early genes in the striatum in response to cocaine and Delta9-tetrahydrocannabinol and for the rewarding properties of these drugs. Here we show that in mice a single injection of cocaine (10 mg/kg) activates mitogen- and stress-activated protein kinase 1 (MSK1) in dorsal striatum and nucleus accumbens. Cocaine-induced phosphorylation of MSK1 threonine 581 and cAMP response element-binding protein (CREB) serine 133 (Ser133) were blocked by SL327, a drug that prevents ERK activation. Cocaine increased the acetylation of histone H4 lysine 5 and phosphorylation of histone H3 Ser10, 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 D1 or D2 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.
Insights
Mitogen- and stress-activated protein kinase 1 (MSK1) is crucial for cocaine-induced gene expression and behavioral changes in mice. Blocking MSK1 affects histone modifications and alters cocaine sensitivity and locomotor sensitization.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Persistent behavioral changes from drug abuse involve gene transcription, but specific signaling pathways are largely unknown.
- Extracellular signal-regulated kinase (ERK) is vital for immediate-early gene expression in the striatum and drug reward.
- Understanding these pathways is key to developing targeted addiction therapies.
Purpose of the Study:
- To investigate the role of mitogen- and stress-activated protein kinase 1 (MSK1) in the intracellular signaling pathways of cocaine-induced gene regulation and behavioral alterations.
- To determine if MSK1 mediates cocaine-induced chromatin remodeling and specific gene induction in the mouse striatum.
Main Methods:
- Administered cocaine (10 mg/kg) to mice and analyzed MSK1 and CREB phosphorylation in the striatum.
- Utilized SL327 to block ERK activation and assess its effect on MSK1 and CREB.
- Examined histone modifications (acetylation and phosphorylation) in response to cocaine.
- Compared cocaine effects in wild-type and MSK1 knockout (KO) mice, assessing gene induction and behavioral responses (conditioned place preference, locomotor sensitization).
Main Results:
- Cocaine activated MSK1 and CREB phosphorylation in the striatum; this was blocked by SL327.
- Cocaine induced histone H4 acetylation and H3 phosphorylation, indicating chromatin remodeling.
- MSK1-KO mice showed blocked CREB and H3 phosphorylation, and prevented induction of c-Fos and dynorphin, but not Egr-1.
- MSK1-KO mice exhibited altered behavioral responses to cocaine, including increased sensitivity to low doses and decreased locomotor sensitization.
Conclusions:
- MSK1 is a key striatal kinase downstream of ERK, essential for CREB and histone H3 phosphorylation.
- MSK1 is specifically required for the induction of c-Fos and dynorphin following cocaine exposure.
- MSK1 plays a critical role in mediating cocaine-induced locomotor sensitization and modifying behavioral responses to the drug.
