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, Lih Chu Chiou

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish
Article number12199
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Jul 22 2016

Fingerprint

Endocannabinoids
Ventral Tegmental Area
Dopaminergic Neurons
neurons
Cocaine
Neurons
Lipoprotein Lipase
Recurrence
Type C Phospholipases
Gq-G11 GTP-Binding Protein alpha Subunits
Orexin Receptors
Cannabinoid Receptors
rodents
gamma-Aminobutyric Acid
releasing
Protein C
mice
Rodentia
cascades
drugs

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. / Tung, Li Wei; Lu, Guan Ling; Lee, Yen Hsien; Yu, Lung; Lee, Hsin Jung; Leishman, Emma; Bradshaw, Heather; Hwang, Ling Ling; Hung, Ming Shiu; MacKie, Ken; Zimmer, Andreas; Chiou, Lih Chu.

In: Nature Communications, Vol. 7, 12199, 22.07.2016.

Research output: Contribution to journalArticle

Tung, LW, Lu, GL, Lee, YH, Yu, L, Lee, HJ, Leishman, E, Bradshaw, H, Hwang, LL, Hung, MS, MacKie, K, Zimmer, A & Chiou, LC 2016, 'Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons', Nature Communications, vol. 7, 12199. https://doi.org/10.1038/ncomms12199
Tung, Li Wei ; Lu, Guan Ling ; Lee, Yen Hsien ; Yu, Lung ; Lee, Hsin Jung ; Leishman, Emma ; Bradshaw, Heather ; Hwang, Ling Ling ; Hung, Ming Shiu ; MacKie, Ken ; Zimmer, Andreas ; Chiou, Lih Chu. / Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. In: Nature Communications. 2016 ; Vol. 7.
@article{9a7c34a0a1674e2f939295ab66948afe,
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.",
author = "Tung, {Li Wei} and Lu, {Guan Ling} and Lee, {Yen Hsien} and Lung Yu and Lee, {Hsin Jung} and Emma Leishman and Heather Bradshaw and Hwang, {Ling Ling} and Hung, {Ming Shiu} and Ken MacKie and Andreas Zimmer and Chiou, {Lih Chu}",
year = "2016",
month = "7",
day = "22",
doi = "10.1038/ncomms12199",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons

AU - Tung, Li Wei

AU - Lu, Guan Ling

AU - Lee, Yen Hsien

AU - Yu, Lung

AU - Lee, Hsin Jung

AU - Leishman, Emma

AU - Bradshaw, Heather

AU - Hwang, Ling Ling

AU - Hung, Ming Shiu

AU - MacKie, Ken

AU - Zimmer, Andreas

AU - Chiou, Lih Chu

PY - 2016/7/22

Y1 - 2016/7/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84979261652&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84979261652&partnerID=8YFLogxK

U2 - 10.1038/ncomms12199

DO - 10.1038/ncomms12199

M3 - Article

AN - SCOPUS:84979261652

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 12199

ER -