title: Knockout of ERK1 enhances cocaine-evoked immediate early gene expression and behavioral plasticity.
abstract: The ability of cocaine to produce lasting neural adaptations in mesocorticolimbic brain regions is thought to promote drug seeking and facilitate addiction in humans. The Ras-controlled Raf-MEK-ERK protein kinase signaling cascade has been implicated in the behavioral and neurobiological actions of cocaine in animals. However, these pharmacological studies have not been able to determine the specific role of the two predominant isoforms of ERK (ERK1 and ERK2) in these processes. We report here that deletion of the ERK1 isoform, which leads to increased ERK2 stimulus-dependent signaling, facilitates the development of cocaine-induced psychomotor sensitization and the acquisition of a cocaine conditioned place preference. Conversely, pharmacological blockade of ERK signaling attenuates the development of psychomotor sensitization to cocaine. Finally, cocaine-evoked gene expression in mesocorticolimbic brain regions is potentiated in ERK1-deficient mice. Thus, alterations in ERK signaling influence both the neurobiological impact of cocaine and its ability to produce enduring forms of drug experience-dependent behavioral plasticity. Our results suggest that enhanced ERK2 signaling following repeated drug exposure may facilitate the development of forms of cocaine-induced plasticity that contribute to addiction.
authors.affiliation: Neuroscience Program, University of Michigan, Ann Arbor, MI 48109-1109, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ferguson
authors.forename: Stefania
authors.initials: S
authors.lastname: Fasano
authors.forename: Pengwei
authors.initials: P
authors.lastname: Yang
authors.forename: Riccardo
authors.initials: R
authors.lastname: Brambilla
authors.forename: Terry E
authors.initials: TE
authors.lastname: Robinson
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003042:Cocaine / Q000009:adverse effects*; D019970:Cocaine-Related Disorders / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects; D004745:Enkephalins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D017781:Genes, Immediate-Early / Q000187:drug effects* / Q000235:genetics; D008032:Limbic System / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000235:genetics; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology
chemical_list: D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D004791:Enzyme Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D003042:Cocaine