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Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2

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Abstract

Rationale

Early life stress is a major risk factor for cocaine addiction; however, the underlying molecular mechanisms remain relatively unexplored. MicroRNA-212 (miR-212) and methyl CpG binding protein 2 (MeCP2) have recently emerged as key regulators of brain-derived neurotrophic factor (BDNF) signaling during the acquisition and maintenance of cocaine-seeking behaviors.

Objectives

We therefore investigated the effect of maternal separation (MS) on cocaine-induced conditioned place preference (CPP) during periadolescence and how this influences miR-212, Mecp2, and Bdnf expressions in the prefrontal cortex.

Methods

Male BALB/c mice subjected to MS (3 h/day) from postnatal day 2 to 15 or normal animal facility rearing (AFR) were tested for CPP at postnatal day 45, or not exposed to experimental manipulations (drug-naïve animals). Cultured primary cortical neurons were used to determine miR-212 expression changes following depolarization by KCL treatment.

Results

MS increased cocaine-induced CPP and decreased Bdnf exon IV expression, which correlated with higher CPP scores in such animals. An experience-dependent decrease in miR-212 expression was observed following CPP test. This effect was mimicked in primary cortical neurons in vitro, under activity-dependent conditions. In contrast, increased Mecp2 expression was found after CPP test, suggesting an opposing relationship between miR-212 and Mecp2 expression following cocaine place preference acquisition. However, these effects were not present in mice exposed to MS.

Conclusions

Together, our results suggest that early life stress can enhance the motivational salience for cocaine-paired cues during periadolescence, and that altered expression of miR-212, Mecp2, and Bdnf in the prefrontal cortex is involved in this process.

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Authors and Affiliations

  1. Postgraduate Program in Pediatrics and Child Health, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil

    Thiago Wendt Viola, Luis Eduardo Wearick-Silva & Rodrigo Grassi-Oliveira

  2. Developmental Cognitive Neuroscience Lab (DCNL), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Avenida Ipiranga, 6681, prédio 11, sala 928, Porto Alegre, 90619-900, RS, Brazil

    Thiago Wendt Viola, Luis Eduardo Wearick-Silva, Lucas Araújo De Azeredo, Anderson Centeno-Silva & Rodrigo Grassi-Oliveira

  3. Postgraduate Program in Medicine and Health Sciences, PUCRS, Porto Alegre, RS, Brazil

    Lucas Araújo De Azeredo

  4. Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria

    Conor Murphy & Nicolas Singewald

  5. Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California—Irvine, Irvine, 92697, CA, USA

    Paul Marshall, Xiang Li & Timothy W. Bredy

  6. Department of Psychiatry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    Frederico Garcia

  7. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia

    Timothy W. Bredy

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  1. Thiago Wendt Viola
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  2. Luis Eduardo Wearick-Silva
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  3. Lucas Araújo De Azeredo
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  4. Anderson Centeno-Silva
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  5. Conor Murphy
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  6. Paul Marshall
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  7. Xiang Li
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  8. Nicolas Singewald
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  9. Frederico Garcia
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  10. Timothy W. Bredy
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  11. Rodrigo Grassi-Oliveira
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Corresponding author

Correspondence to Rodrigo Grassi-Oliveira.

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The experiments were conducted in accordance with the NIH laboratory animal care guidelines and approved by the Ethical Committee on the Use of Animals of the Pontifical Catholic University of Rio Grande do Sul, Brazil.

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Viola, T.W., Wearick-Silva, L.E., De Azeredo, L.A. et al. Increased cocaine-induced conditioned place preference during periadolescence in maternally separated male BALB/c mice: the role of cortical BDNF, microRNA-212, and MeCP2. Psychopharmacology 233, 3279–3288 (2016). https://doi.org/10.1007/s00213-016-4373-z

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