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

• Published in: Nature communications Vol. 7; no. 1; p. 12199
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 22.07.2016; Nature Portfolio
• Subjects: Action Potentials - drug effects; Animals; Arachidonic Acids - metabolism; Brain research; Cocaine; Cocaine - adverse effects; Conditioning, Classical; Dopamine; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Endocannabinoids - metabolism; Excitatory Postsynaptic Potentials - drug effects; gamma-Aminobutyric Acid - metabolism; Glycerides - metabolism; Hypothalamic Area, Lateral - drug effects; Hypothalamic Area, Lateral - metabolism; Hypothalamus; Inhibitory Postsynaptic Potentials - drug effects; Male; Medical schools; Medicine; Mice, Inbred C57BL; Models, Biological; Morphine; Neural Inhibition - drug effects; Orexin Receptors - metabolism; Orexins - metabolism; Rats, Wistar; Receptor, Cannabinoid, CB1 - agonists; Receptor, Cannabinoid, CB1 - antagonists & inhibitors; Receptor, Cannabinoid, CB1 - metabolism; Recurrence; Restraint, Physical; Signal Transduction - drug effects; Stress, Physiological; Synaptic Transmission - drug effects; Ventral Tegmental Area - drug effects; Ventral Tegmental Area - metabolism; Indiana; United States > US; Taiwan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12199

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.