Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-07-23

AUTHORS

Anna M W Taylor, Annie Castonguay, Atefeh Ghogha, Pia Vayssiere, Amynah A A Pradhan, Lihua Xue, Sadaf Mehrabani, Juli Wu, Pat Levitt, Mary C Olmstead, Yves De Koninck, Christopher J Evans, Catherine M Cahill

ABSTRACT

Opioid dependence is accompanied by neuroplastic changes in reward circuitry leading to a negative affective state contributing to addictive behaviors and risk of relapse. The current study presents a neuroimmune mechanism through which chronic opioids disrupt the ventral tegmental area (VTA) dopaminergic circuitry that contributes to impaired reward behavior. Opioid dependence was induced in rodents by treatment with escalating doses of morphine. Microglial activation was observed in the VTA following spontaneous withdrawal from chronic morphine treatment. Opioid-induced microglial activation resulted in an increase in brain-derived neurotrophic factor (BDNF) expression and a reduction in the expression and function of the K(+)Cl(-) co-transporter KCC2 within VTA GABAergic neurons. Inhibition of microglial activation or interfering with BDNF signaling prevented the loss of Cl(-) extrusion capacity and restored the rewarding effects of cocaine in opioid-dependent animals. Consistent with a microglial-derived BDNF-induced disruption of reward, intra-VTA injection of BDNF or a KCC2 inhibitor resulted in a loss of cocaine-induced place preference in opioid-naïve animals. The loss of the extracellular Cl(-) gradient undermines GABAA-mediated inhibition, and represents a mechanism by which chronic opioid treatments can result in blunted reward circuitry. This study directly implicates microglial-derived BDNF as a negative regulator of reward in opioid-dependent states, identifying new therapeutic targets for opiate addictive behaviors. More... »

PAGES

949-959

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/npp.2015.221

    DOI

    http://dx.doi.org/10.1038/npp.2015.221

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1011020127

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26202104


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    372 schema:name Department of Anesthesiology and Perioperative Care, University of California, Irvine, CA, USA.
    373 Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
    374 Department of Psychology, Queen's University, Kingston, ON, Canada.
    375 rdf:type schema:Organization
    376 grid-institutes:grid.42505.36 schema:alternateName Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
    377 schema:name Children's Hospital Los Angeles and the Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
    378 rdf:type schema:Organization
     




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