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Adolescence: a time of transition for the phenotype of dcc heterozygous mice

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Abstract

Rationale

Stark differences exist between adult (>PND 70) and juvenile (∼PND 21–34) rodents in how DCC (deleted in colorectal cancer) receptors and sensitization to amphetamine interact. In adults, repeated amphetamine upregulates DCC receptor expression selectively in the ventral tegmental area (VTA), an effect that is critical for sensitization. In contrast, amphetamine administered to juveniles downregulates VTA DCC expression. Moreover, whereas adult dcc heterozygous mice fail to sensitize when repeatedly treated with amphetamine, drug treatment during the juvenile period actually abolishes this adult “protective” phenotype.

Objectives

We set out to determine whether adolescence (PND ∼35–55) is a period during which: (1) amphetamine-induced alterations in VTA DCC expression switch from downregulation to upregulation; (2) the “protective” phenotype of adult dcc heterozygotes against sensitization becomes evident; and (3) the adult “protective” phenotype of dcc heterozygotes can still be abolished by repeated amphetamine treatment.

Results

Repeated amphetamine did not significantly alter VTA DCC expression in adolescent rodents when assessed 1 week later. Both wild-type and dcc heterozygous mice exhibited sensitization at this time. Remarkably, wild-type mice, but not dcc heterozygotes, exhibited sensitization when tested during adulthood.

Conclusions

Adolescence is a time of transition for dcc heterozygotes as related to sensitization. Our results support the hypothesis that DCC may be a key factor in determining age-dependent individual differences in vulnerability to sensitization. Given that exposure to drugs of abuse during adolescence can have profound consequences for adulthood, the resilience of adult dcc heterozygous mice against adolescent exposure to amphetamine is particularly salient.

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Acknowledgments

We thank 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. This work was funded by the Natural Science and Engineering Research Council of Canada, the Canadian Institutes of Health Research, 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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The authors declare that they have no conflict of interests.

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Correspondence to Cecilia Flores.

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Yetnikoff, L., Pokinko, M., Arvanitogiannis, A. et al. Adolescence: a time of transition for the phenotype of dcc heterozygous mice. Psychopharmacology 231, 1705–1714 (2014). https://doi.org/10.1007/s00213-013-3083-z

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  • DOI: https://doi.org/10.1007/s00213-013-3083-z

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