Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition

Ja Wook Koo, Mary Kay Lobo, Dipesh Chaudhury, Benoit Labonté, Allyson Friedman, Elizabeth Heller, Catherine Jensen Peña, Ming Hu Han, Eric J. Nestler

    Research output: Contribution to journalArticle

    Abstract

    The nucleus accumbens (NAc) has a central role in the mechanism of action of drugs of abuse. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), with two major subpopulations defined - termed D1-type and D2-type MSNs - based on the predominant dopamine receptor expressed. However, very little is known about the contribution of altered GABAergic function in NAc MSNs to the neural and behavioral plasticity that contributes to the lasting actions of drugs of abuse. In the present study, we show that GABAergic activity is selectively modulated in D1-type MSNs of the NAc by signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB), and that such adaptations control rewarding responses to morphine. Optical activation of D1-type MSNs, or the knockout of TrkB from D1-type MSNs (D1-TrkB KO), enhances morphine reward, effects not seen for D2-type MSNs. In addition, D1-TrkB KO mice, but not D2-TrkB KO mice, display decreased GABAA receptor (GABAAR) subunit expression and reduced spontaneous inhibitory postsynaptic currents (sIPSCs) in D1-type, but not D2-type, MSNs in the NAc. Furthermore, we found that GABAAR antagonism in the NAc enhances morphine reward and that morphine exposure decreases TrkB expression as well as GABAergic activity in D1-type MSNs. Together, these data provide evidence for the enhancement of morphine reward through reduction of inhibitory GABA A R responses, an adaptation mediated by morphine-induced reduction of BDNF-TrkB signaling in D1-type MSNs.

    Original languageEnglish (US)
    Pages (from-to)2646-2653
    Number of pages8
    JournalNeuropsychopharmacology
    Volume39
    Issue number11
    DOIs
    StatePublished - Oct 1 2014

    Fingerprint

    Brain-Derived Neurotrophic Factor
    Nucleus Accumbens
    Receptor Protein-Tyrosine Kinases
    Reward
    gamma-Aminobutyric Acid
    Morphine
    Neurons
    trkB Receptor
    Street Drugs
    GABA-A Receptors
    Inhibitory Postsynaptic Potentials
    Neuronal Plasticity
    Dopamine Receptors
    Protein-Tyrosine Kinases
    Inhibition (Psychology)

    ASJC Scopus subject areas

    • Pharmacology
    • Psychiatry and Mental health

    Cite this

    Koo, J. W., Lobo, M. K., Chaudhury, D., Labonté, B., Friedman, A., Heller, E., ... Nestler, E. J. (2014). Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition. Neuropsychopharmacology, 39(11), 2646-2653. https://doi.org/10.1038/npp.2014.118

    Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition. / Koo, Ja Wook; Lobo, Mary Kay; Chaudhury, Dipesh; Labonté, Benoit; Friedman, Allyson; Heller, Elizabeth; Peña, Catherine Jensen; Han, Ming Hu; Nestler, Eric J.

    In: Neuropsychopharmacology, Vol. 39, No. 11, 01.10.2014, p. 2646-2653.

    Research output: Contribution to journalArticle

    Koo, JW, Lobo, MK, Chaudhury, D, Labonté, B, Friedman, A, Heller, E, Peña, CJ, Han, MH & Nestler, EJ 2014, 'Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition', Neuropsychopharmacology, vol. 39, no. 11, pp. 2646-2653. https://doi.org/10.1038/npp.2014.118
    Koo, Ja Wook ; Lobo, Mary Kay ; Chaudhury, Dipesh ; Labonté, Benoit ; Friedman, Allyson ; Heller, Elizabeth ; Peña, Catherine Jensen ; Han, Ming Hu ; Nestler, Eric J. / Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition. In: Neuropsychopharmacology. 2014 ; Vol. 39, No. 11. pp. 2646-2653.
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