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Nat Commun. 2016 Jul 22;7:12199. doi: 10.1038/ncomms12199.

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

Author information

1
Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
2
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan.
3
Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, No.1, University Road, Tainan City 70101, Taiwan.
4
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
5
Gill Center and the Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, USA.
6
Department of Physiology, College of Medicine, Taipei Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan.
7
Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
8
Institute for Molecular Psychiatry, Medical Faculty, University of Bonn, 53127 Bonn, Germany.
9
Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
10
Research Center for Chinese Medicine &Acupuncture, China Medical University, Taichung 40447, Taiwan.

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.

PMID:
27448020
PMCID:
PMC4961842
DOI:
10.1038/ncomms12199
[Indexed for MEDLINE]
Free PMC Article

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