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Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons

Author

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  • Li-Wei Tung

    (Graduate Institute of Pharmacology, College of Medicine, National Taiwan University)

  • Guan-Ling Lu

    (Graduate Institute of Pharmacology, College of Medicine, National Taiwan University)

  • Yen-Hsien Lee

    (Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University)

  • Lung Yu

    (Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University)

  • Hsin-Jung Lee

    (College of Medicine, National Taiwan University)

  • Emma Leishman

    (Indiana University)

  • Heather Bradshaw

    (Indiana University)

  • Ling-Ling Hwang

    (Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University
    College of Medicine, Taipei Medical University)

  • Ming-Shiu Hung

    (Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes)

  • Ken Mackie

    (Indiana University)

  • Andreas Zimmer

    (Institute for Molecular Psychiatry, Medical Faculty, University of Bonn)

  • Lih-Chu Chiou

    (Graduate Institute of Pharmacology, College of Medicine, National Taiwan University
    College of Medicine, National Taiwan University
    Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University
    Research Center for Chinese Medicine & Acupuncture, China Medical University)

Abstract

Orexins are associated with drug relapse in rodents. Here, we show that acute restraint stress in mice activates lateral hypothalamic (LH) orexin neurons, increases levels of orexin A and 2-arachidonoylglycerol (2-AG) in the ventral tegmental area (VTA), and reinstates extinguished cocaine-conditioned place preference (CPP). This stress-induced reinstatement of cocaine CPP depends on type 1 orexin receptors (OX1Rs), type 1 cannabinoid receptors (CB1Rs) and diacylglycerol lipase (DAGL) in the VTA. In dopaminergic neurons of VTA slices, orexin A presynaptically inhibits GABAergic transmission. This effect is prevented by internal GDP-β-S or inhibiting OX1Rs, CB1Rs, phospholipase C or DAGL, and potentiated by inhibiting 2-AG degradation. These results suggest that restraint stress activates LH orexin neurons, releasing orexins into the VTA to activate postsynaptic OX1Rs of dopaminergic neurons and generate 2-AG through a Gq-protein-phospholipase C-DAGL cascade. 2-AG retrogradely inhibits GABA release through presynaptic CB1Rs, leading to VTA dopaminergic disinhibition and reinstatement of cocaine CPP.

Suggested Citation

  • Li-Wei Tung & Guan-Ling Lu & Yen-Hsien Lee & Lung Yu & Hsin-Jung Lee & Emma Leishman & Heather Bradshaw & Ling-Ling Hwang & Ming-Shiu Hung & Ken Mackie & Andreas Zimmer & Lih-Chu Chiou, 2016. "Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms12199
    DOI: 10.1038/ncomms12199
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    Cited by:

    1. David Lau & Stephanie Tobin & Horia Pribiag & Shingo Nakajima & Alexandre Fisette & Dominique Matthys & Anna Kristyna Franco Flores & Marie-Line Peyot & S. R. Murthy Madiraju & Marc Prentki & David St, 2024. "ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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