title: Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons.
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.
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Tung
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Guan-Ling
authors.initials: GL
authors.lastname: Lu
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan.
authors.forename: Yen-Hsien
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan City 70101, Taiwan.
authors.forename: Lung
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
authors.forename: Hsin-Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Gill Center and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Leishman
authors.affiliation: Gill Center and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Bradshaw
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan.|Department of Physiology, College of Medicine, Taipei Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan.
authors.forename: Ling-Ling
authors.initials: LL
authors.lastname: Hwang
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Ming-Shiu
authors.initials: MS
authors.lastname: Hung
authors.affiliation: Gill Center and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.affiliation: Institute for Molecular Psychiatry, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 100, Taiwan.|Research Center for Chinese Medicine &Acupuncture, China Medical University, Taichung 40447, Taiwan.
authors.forename: Lih-Chu
authors.initials: LC
authors.lastname: Chiou
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D003042:Cocaine / Q000009:adverse effects*; D003214:Conditioning, Classical; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005989:Glycerides / Q000378:metabolism; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000378:metabolism; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009433:Neural Inhibition / Q000187:drug effects; D064446:Orexin Receptors / Q000378:metabolism; D000068797:Orexins / Q000378:metabolism*; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012008:Recurrence; D012149:Restraint, Physical; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D009435:Synaptic Transmission / Q000187:drug effects; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; C578453:CNR1 protein, mouse; D063388:Endocannabinoids; D005989:Glycerides; D064446:Orexin Receptors; D000068797:Orexins; D043884:Receptor, Cannabinoid, CB1; D005680:gamma-Aminobutyric Acid; C094503:glyceryl 2-arachidonate; D003042:Cocaine