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Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice

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Abstract

Rationale

Previous studies have suggested the involvement of neuronal nitric oxide synthase (nNOS) in the development of sensitization to psychostimulants. Ontogeny-dependent differences in the response to psychostimulants have been reported.

Objective

The objectives were to investigate (a) the short- and long-term consequences of adolescent and adult cocaine exposure on behavioral sensitization and (b) the role of the nNOS gene in behavioral sensitization in adolescent and adult mice.

Materials and methods

Adolescent and adult wild type (WT) and nNOS knockout (KO) mice received saline or cocaine (20 mg/kg) for 5 days and then were challenged with cocaine (20 mg/kg) after a drug-free period of 10 or 30 days. Locomotor activity was recorded by infrared beam interruptions. nNOS immunoreactive (ir) neurons in the dorsal and ventral striatum were quantified 24 h after repeated administration of cocaine to adolescent and adult WT mice.

Results

Repeated administration of cocaine to either WT or nNOS KO mice during adolescence resulted in locomotor sensitization, which persisted into adulthood. WT but not KO adult mice developed long-term sensitization to cocaine. Repeated cocaine administration resulted in a 96% increase in the expression of nNOS-ir neurons in the dorsal striatum of adult but not adolescent WT mice.

Conclusions

The nNOS gene is essential for the induction of behavioral sensitization to cocaine in adulthood but not in adolescence. The increased expression of nNOS-ir neurons in the dorsal striatum may underlie the induction of behavioral sensitization in adulthood. Thus, the NO-signaling pathway has an ontogeny-dependent role in the neuroplasticity underlying cocaine behavioral sensitization.

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Acknowledgments

This work was supported by awards RO1 DA019107 (YI) and F30 DA022847-01 (MB) from the National Institute on Drug Abuse. The authors are thankful to Dr. Chuanhui Dong, Dept. of Psychiatry & Behavioral Sciences, University of Miami School of Medicine, for his assistance in the statistical analysis.

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Authors and Affiliations

  1. Neuroscience Program, University of Miami School of Medicine, Miami, FL, USA

    Mara A. Balda & Yossef Itzhak

  2. Department of Psychiatry and Behavioral Sciences, University of Miami School of Medicine, Gautier Building Room # 503, 1011 NW 15th Street, Miami, FL, 33136, USA

    Karen L. Anderson & Yossef Itzhak

Authors
  1. Mara A. Balda
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  2. Karen L. Anderson
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  3. Yossef Itzhak
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Correspondence to Yossef Itzhak.

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Balda, M.A., Anderson, K.L. & Itzhak, Y. Differential role of the nNOS gene in the development of behavioral sensitization to cocaine in adolescent and adult B6;129S mice. Psychopharmacology 200, 509–519 (2008). https://doi.org/10.1007/s00213-008-1228-2

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  • DOI: https://doi.org/10.1007/s00213-008-1228-2

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