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Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period

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Abstract

Rationale

Netrin-1 guidance cues contribute to amphetamine-induced plasticity of the adult mesocorticolimbic dopamine system in rodents. The netrin-1 receptor, deleted in colorectal cancer (DCC), is upregulated by repeated amphetamine treatment selectively in the ventral tegmental area (VTA) of adult rats and wild-type mice. Furthermore, adult dcc heterozygous mice fail to show amphetamine-induced increases in VTA DCC expression and do not develop sensitization to this drug.

Objectives

The effects of netrin-1 receptor signaling on mesocorticolimbic dopamine system function change across development. However, the effects of AMPH on DCC receptor regulation and behavioral sensitization before puberty have not been determined. Here we examined whether (1) repeated amphetamine treatment would also alter DCC expression in juvenile rats and wild-type mice, and (2) dcc heterozygotes treated with amphetamine during the juvenile period (PND 22–32) would develop behavioral sensitization to this drug.

Results

Repeated amphetamine downregulates DCC expression selectively in the VTA of juvenile rodents. Moreover, the behavioral phenotype of adult dcc heterozygous mice is not present before puberty and is abolished by amphetamine treatment during the juvenile period. Remarkably, adult dcc heterozygotes pretreated with amphetamine as juveniles no longer exhibit reduced DCC expression in the VTA compared to wild-type controls.

Conclusions

Our results indicate that netrin-1 receptor signaling may be a key factor in determining individual differences in vulnerability to the behaviorally sensitizing effects of amphetamine at different ages. Moreover, they suggest that the juvenile period marks a window of vulnerability during which exposure to stimulant drugs can reverse the behavioral phenotype of adult dcc heterozygous mice.

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Acknowledgments

We thank Jane Stewart for critical reading of the manuscript and Susan Ackerman (The Jackson Laboratory) for the original dcc heterozygous breeders. All experimental procedures were performed in accordance with the guidelines of the Canadian Council on Animal Care, the Animal Committee of the Douglas Mental Health University Institute/McGill University, and the Concordia University Animal Research Ethics Committee.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Author information

Authors and Affiliations

  1. Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada

    Leora Yetnikoff & Cecilia Flores

  2. Department of Psychiatry, McGill University, Montréal, QC, Canada

    Cecilia Flores

  3. Douglas Mental Health University Institute, (Perry Pavilion, room# 2111) 6875 LaSalle Blvd, Montréal (Verdun), QC, H4H 1R3, Canada

    Cecilia Flores

  4. Department of Psychology, Center for Studies in Behavioral Neurobiology, Concordia University, Montréal, QC, Canada

    Anne Almey & Andreas Arvanitogiannis

Authors
  1. Leora Yetnikoff
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  2. Anne Almey
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  4. Cecilia Flores
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Corresponding author

Correspondence to Cecilia Flores.

Additional information

This work was funded by the Natural Science and Engineering Research Council of Canada, the Fonds de la Recherche en Santé du Québec, and the Fonds Québécois de la Recherche sur la Nature et les Technologies.

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Yetnikoff, L., Almey, A., Arvanitogiannis, A. et al. Abolition of the behavioral phenotype of adult netrin-1 receptor deficient mice by exposure to amphetamine during the juvenile period. Psychopharmacology 217, 505–514 (2011). https://doi.org/10.1007/s00213-011-2312-6

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  • DOI: https://doi.org/10.1007/s00213-011-2312-6

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