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

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 and Lih-Chu Chiou ()
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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
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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12199

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