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Author Notes:

Anthony J. Koleske, 333 Cedar Street, SHMC-E31, New Haven, CT 06520-8024. anthony.koleske@yale.edu.

S.L.G., M.S.W., J.R.T., and A.J.K. designed research; S.L.G. and A.O. performed research; S.L.G. and J.R.T. analyzed data; S.L.G., J.R.T., and A.J.K. wrote the paper.

We thank Drs. G. Aghajanian, A. Nairn, and Y.-C. Lin for advice and feedback, and X.-Y. Ye, J. Gordon, and M. Kerrisk for their valuable assistance.

We are grateful to Dr. W. Bornmann for STI-571, Dr. J. Settleman for p190RhoGAP mutant mice, and Dr. S. Goff for Abl mutant mice.

A.J.K. is an Established Investigator of the American Heart Association.

The authors declare no competing financial interests.

Subjects:

Research Funding:

This work was supported by the Connecticut Mental Health and Addiction Services, Children's Healthcare of Atlanta, the Interdisciplinary Research Consortium on Stress, Self-Control, and Addiction (IRCSSA) (Grant UL1-DE19586 and NIH Roadmap for Medical Research/Common Fund Grant AA017537), and the IRCSSA Interdisciplinary Research Education [RL5; Carolyn M. Mazure (Yale University, New Haven, CT), principal investigator] Program Grant 1RL5DA024858.

We also acknowledge United States Public Health Service Grants NS039475, CA133346 (A.J.K.), DA027844, and DA011717 (J.R.T.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Neurosciences & Neurology
  • VENTRAL TEGMENTAL AREA
  • ORBITOFRONTAL CORTEX
  • NUCLEUS-ACCUMBENS
  • BEHAVIORAL SENSITIZATION
  • DEPENDENT REGULATION
  • CORTICAL DEVELOPMENT
  • PYRAMIDAL NEURON
  • CEREBRAL-CORTEX
  • CRITICAL PERIOD
  • FAMILY KINASES

Arg Kinase Regulates Prefrontal Dendritic Spine Refinement and Cocaine-Induced Plasticity

Tools:

Journal Title:

Journal of Neuroscience Nursing

Volume:

Volume 32, Number 7

Publisher:

, Pages 2314-2323

Type of Work:

Article | Final Publisher PDF

Abstract:

Adolescence is characterized by vulnerability to the development of neuropsychiatric disorders including drug addiction, as well as prefrontal cortical refinement that culminates in structural stability in adulthood. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, although intracellular mechanisms are largely unknown. We characterized layer V prefrontal dendritic spine development and refinement in adolescent wild-type mice and mice lacking the cytoskeletal regulatory protein Abl-related gene (Arg) kinase. Relative to hippocampal CA1 pyramidal neurons, which exhibited a nearly linear increase in spine density up to postnatal day 60 (P60), wild-type prefrontal spine density peaked at P31, and then declined by 18% by P56-P60. In contrast, dendritic spines in mice lacking Arg destabilized by P31, leading to a net loss in both structures. Destabilization corresponded temporally to the emergence of exaggerated psychomotor sensitivity to cocaine. Moreover, cocaine reduced dendritic spine density in wild-type orbitofrontal cortex and enlarged remaining spine heads, but arg_/_spines were unresponsive. Local application of Arg or actin polymerization inhibitors exaggerated cocaine sensitization, as did reduced gene dosage of the Arg substrate, p190RhoGAP. Genetic and pharmacological Arg inhibition also retarded instrumental reversal learning and potentiated responding for reward-related cues, providing evidence that Arg regulates both psychomotor sensitization and decision-making processes implicated in addiction. These findings also indicate that structural refinement in the adolescent orbitofrontal cortex mitigates psychostimulant sensitivity and support the emerging perspective that the structural response to cocaine may, at any age, have behaviorally protective consequences.

Copyright information:

© 2012 the authors.

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