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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Action Potentials / drug effects
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Animals
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Arachidonic Acids / metabolism
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Cocaine / adverse effects*
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Conditioning, Classical
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / metabolism*
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Endocannabinoids / metabolism*
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Excitatory Postsynaptic Potentials / drug effects
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Glycerides / metabolism
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Hypothalamic Area, Lateral / drug effects
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Hypothalamic Area, Lateral / metabolism
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Inhibitory Postsynaptic Potentials / drug effects
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Male
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Mice, Inbred C57BL
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Models, Biological
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Neural Inhibition* / drug effects
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Orexin Receptors / metabolism
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Orexins / metabolism*
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Rats, Wistar
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Receptor, Cannabinoid, CB1 / agonists
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors
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Receptor, Cannabinoid, CB1 / metabolism
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Recurrence
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Restraint, Physical*
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Signal Transduction / drug effects
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Stress, Physiological*
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Synaptic Transmission / drug effects
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Ventral Tegmental Area / drug effects
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Ventral Tegmental Area / metabolism
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gamma-Aminobutyric Acid / metabolism
Substances
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Arachidonic Acids
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CNR1 protein, mouse
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Endocannabinoids
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Glycerides
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Orexin Receptors
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Orexins
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Receptor, Cannabinoid, CB1
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gamma-Aminobutyric Acid
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glyceryl 2-arachidonate
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Cocaine