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Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids

Molecular Psychiatry volume 17, pages 1295–1305 (2012)Cite this article

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Abstract

Stress and exposure to glucocorticoids (GC) during early life render individuals vulnerable to brain disorders by inducing structural and chemical alterations in specific neural substrates. Here we show that adult rats that had been exposed to in utero GCs (iuGC) display increased preference for opiates and ethanol, and are more responsive to the psychostimulatory actions of morphine. These animals presented prominent changes in the nucleus accumbens (NAcc), a key component of the mesolimbic reward circuitry; specifically, cell numbers and dopamine (DA) levels were significantly reduced, whereas DA receptor 2 (Drd2) mRNA expression levels were markedly upregulated in the NAcc. Interestingly, repeated morphine exposure significantly downregulated Drd2 expression in iuGC-exposed animals, in parallel with increased DNA methylation of the Drd2 gene. Administration of a therapeutic dose of L-dopa reverted the hypodopaminergic state in the NAcc of iuGC animals, normalized Drd2 expression and prevented morphine-induced hypermethylation of the Drd2 promoter. In addition, L-dopa treatment promoted dendritic and synaptic plasticity in the NAcc and, importantly, reversed drug-seeking behavior. These results reveal a new mechanism through which drug-seeking behaviors may emerge and suggest that a brief and simple pharmacological intervention can restrain these behaviors in vulnerable individuals.

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Acknowledgements

We would like to thank the members of the Neuroscience Research Domain at ICVS for all the helpful discussions and suggestions. We are especially thankful to the animal facility caretakers, and to Drs Sara Silva, António Melo and Ana Paula Silva and Dieter Fischer for their help. This work was supported by the Institute for the Study of Affective Neuroscience (ISAN). AJR, BC and MC were supported by Fundação para a Ciência e Tecnologia (FCT) fellowships.

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  1. A J Rodrigues and P Leão: These authors contributed equally to this work.

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal

    A J Rodrigues, P Leão, J M Pêgo, D Cardona, M M Carvalho, M Oliveira, B M Costa, A F Carvalho, P Morgado, D Araújo, J A Palha & N Sousa

  2. ICVS/3B's–PT Government Associate Laboratory, Braga/Guimarães, Portugal

    A J Rodrigues, P Leão, J M Pêgo, D Cardona, M M Carvalho, M Oliveira, B M Costa, A F Carvalho, P Morgado, D Araújo, J A Palha & N Sousa

  3. Neuroadaptations Group, Max Planck Institute of Psychiatry, Munich, Germany

    O F X Almeida

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Correspondence to N Sousa.

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Rodrigues, A., Leão, P., Pêgo, J. et al. Mechanisms of initiation and reversal of drug-seeking behavior induced by prenatal exposure to glucocorticoids. Mol Psychiatry 17, 1295–1305 (2012). https://doi.org/10.1038/mp.2011.126

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