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Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats

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Abstract

Rationale

Environmental challenges during adolescence, such as drug exposure, can cause enduring behavioral and molecular changes that contribute to life-long maladaptive behaviors, including addiction. Selectively bred high-responder (bHR) and low-responder (bLR) rats represent a unique model for assessing the long-term impact of adolescent environmental manipulations, as they inherently differ on a number of addiction-related traits. bHR rats are considered “addiction-prone,” whereas bLR rats are “addiction-resilient,” at least under baseline conditions. Moreover, relative to bLRs, bHR rats are more likely to attribute incentive motivational value to reward cues, or to “sign-track.”

Objectives

We utilized bHR and bLR rats to determine whether adolescent cocaine exposure can alter their inborn behavioral and neurobiological profiles, with a specific focus on Pavlovian conditioned approach behavior (i.e., sign- vs. goal-tracking) and hippocampal neurogenesis.

Methods

bHR and bLR rats were administered cocaine (15 mg/kg) or saline for 7 days during adolescence (postnatal day, PND 33–39) and subsequently tested for Pavlovian conditioned approach behavior in adulthood (PND 62–75), wherein an illuminated lever (conditioned stimulus) was followed by the response-independent delivery of a food pellet (unconditioned stimulus). Behaviors directed toward the lever and the food cup were recorded as sign- and goal-tracking, respectively. Hippocampal cell genesis was evaluated on PND 77 by immunohistochemistry.

Results

Adolescent cocaine exposure impaired hippocampal cell genesis (proliferation and survival) and enhanced the inherent propensity to goal-track in adult bLR, but not bHR, rats.

Conclusions

Adolescent cocaine exposure elicits long-lasting changes in stimulus-reward learning and enduring deficits in hippocampal neurogenesis selectively in adult bLR rats.

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Acknowledgements

This work was funded in part by the National Institute of Drug Abuse 5P01DA021633, T32 DA007268 and Office of Naval Research N00014-09-1-0598, N00014-12-1-0366 to H.A. This work was also funded by “Delegación del Gobierno para el Plan Nacional sobre Drogas, Ministerio de Sanidad, Servicios Sociales e Igualdad” (grants 2012/011 and 2016/002, Spain) and “Fundación Alicia Koplowitz” to M.J.G.-F as well as by RETICS-RTA (RD12/0028/0011; Instituto de Salud Carlos III, MINECO/FEDER, Spain). M.J.G.-F. is a “Ramón y Cajal” Researcher (MINECO-UIB). A.P. was supported by the Biology of Drug Abuse Postdoctoral Training Program (University of Michigan Medical School, grant T32 DA007268). We would like to thank Jonathan D. Morrow for comments on earlier versions of the manuscript as well as Peter Blandino for oversight of the selective-breeding colony, and Angela Koelsch and Jennifer Fitzpatrick for their technical assistance.

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Authors and Affiliations

  1. IUNICS/IdISPa, University of the Balearic Islands, Cra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain

    M. Julia García-Fuster

  2. Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA

    Aram Parsegian, Stanley J. Watson, Huda Akil & Shelly B. Flagel

  3. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    Stanley J. Watson, Huda Akil & Shelly B. Flagel

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  1. M. Julia García-Fuster
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  2. Aram Parsegian
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  3. Stanley J. Watson
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  4. Huda Akil
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  5. Shelly B. Flagel
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Corresponding author

Correspondence to M. Julia García-Fuster.

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Ethical standards

The experiments were carried out following the Guide for the Care and Use of Laboratory Animals: Eighth Edition, revised 2011, published by the National Academy of Sciences, and all procedures were approved by the University of Michigan University Committee for the Use and Care of Animals.

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The authors declare the absence of any competing financial interests concerning the content of this document.

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M.J.G.-F. and A.P. contributed equally to this publication.

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García-Fuster, M.J., Parsegian, A., Watson, S.J. et al. Adolescent cocaine exposure enhances goal-tracking behavior and impairs hippocampal cell genesis selectively in adult bred low-responder rats. Psychopharmacology 234, 1293–1305 (2017). https://doi.org/10.1007/s00213-017-4566-0

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