ArticleNature communications2016
Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons.
Article in Nature communications, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 125 citations in OpenAlex.
- Neuropeptide S modulation of learning and memory: a systematic review.Behavioral and brain functions : BBF · 2026Pooled it
- Functional Plasticity of Orexin/Hypocretin Neurons Balances Stress States.Biological psychiatry · 2026Review
- Sleep regulates drug seeking and relapse - a perspective.Molecular psychiatry · 2026Review
- Central neuropeptides as key modulators of astrocyte function in neurodegenerative and neuropsychiatric disorders.Psychopharmacology · 2025Review
- The Orexin System in Addiction: Neuromodulatory Interactions and Therapeutic Potential.Brain sciences · 2025Review
- Counterbalancing O-GlcNAcylation and STAT3 Phosphorylation in Ventral Tegmental Area Dopaminergic Neurons Mediates Behavioral Adaptations to Acute Restraint Stress.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Orexinergic projections to substantia innominata mediate arousal and analgesia.British journal of anaesthesia · 2025Article
- The Complexly Parcellated, Yet Quantitatively Reduced, Orexinergic/Hypocretinergic System of Humans.The Journal of comparative neurology · 2025Article
- Article
- Chronic alcohol withdrawal-associated increases in VTAAdvances in drug and alcohol research · 2025Article
- ABHD6 loss-of-function in mesoaccumbens postsynaptic but not presynaptic neurons prevents diet-induced obesity in male mice.Nature communications · 2024Article
- G protein-coupled receptor modulation of striatal dopamine transmission: Implications for psychoactive drug effects.British journal of pharmacology · 2024Review
- Contribution of hypothalamic orexin (hypocretin) circuits to pathologies of motivation.British journal of pharmacology · 2024Review
- Interaction between corticotropin-releasing factor, orexin, and dynorphin in the infralimbic cortex may mediate exacerbated alcohol-seeking behavior.Neurobiology of stress · 2024Article
- Distinct Neuromodulatory Effects of Endogenous Orexin and Dynorphin Corelease on Projection-Defined Ventral Tegmental Dopamine Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- The Role of Orexin Receptor Antagonists in Inhibiting Drug Addiction: A Review Article.Addiction & health · 2024Review
- Lateral hypothalamus orexinergic projection to the medial prefrontal cortex modulates chronic stress-induced anhedonia but not anxiety and despair.Translational psychiatry · 2024Article
- Article
- Role of mesolimbic cannabinoid receptor 1 in stress-driven increases in cocaine self-administration in male rats.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Endocannabinoid signaling and epigenetics modifications in the neurobiology of stress-related disorders.Neuronal signaling · 2023Review
Corrections and comments
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Authors and funding
12 authors at 6 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.