ArticleProceedings of the National Academy of Sciences of the United States of America2014
Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 160 papers.
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160 citing papers in PubMed, 260 citations in OpenAlex.
- An opto-microperfusion neural probe for multiplexed detection of optogenetically evoked neurochemical release dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Hypothalamic control of arousal.Reviews in endocrine & metabolic disorders · 2026Review
- Functional interaction between orexin/CRF and orexin/dynorphin transmission in the infralimbic cortex modulates the stress-induced reinstatement of alcohol-seeking behavior in male and female Wistar rats.Neuropharmacology · 2026Article
- Hypocretin receptor 1 blockade early in abstinence prevents incubation of cocaine seeking and normalizes dopamine transmission.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Sleep regulates drug seeking and relapse - a perspective.Molecular psychiatry · 2026Review
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- Kappa opioid receptor control of motivated behavior revisited.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Review
- Chemical multiplexing in the nervous system: molecular architecture, functional stratification, and pathophysiological plasticity of neuropeptide-classical neurotransmitter cotransmission.Frontiers in molecular neuroscience · 2026Review
- Lateral hypothalamic orexinergic neurons as central mediators of pain modulation and non-pharmacological analgesia.Frontiers in pharmacology · 2026Review
- Modulatory effects of orexin and dynorphin on stress-related alcohol seeking and relapse: pivotal role of the posterior paraventricular nucleus of the thalamus.Frontiers in pharmacology · 2026Review
- Coordinated infraslow cortical oscillations of neuromodulators during NREM sleep.bioRxiv : the preprint server for biology · 2025Article
- Review
- Repeated Morphine Exposure Reversibly Impairs Spike Generation and Repetitive Firing in a Functionally Distinct Subpopulation of Orexin Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025Article
- Hypocretin signaling in the central amygdala drives methamphetamine self-administration in male rats.Neuropharmacology · 2025Article
- Drug-Related Engrams and Their Role in the Persistence and Recurrence of Drug-Related Behaviors.Hippocampus · 2025Review
- The Orexin System in Addiction: Neuromodulatory Interactions and Therapeutic Potential.Brain sciences · 2025Review
- Melanin-Concentrating Hormone (MCH): Role in Mediating Reward-Motivated and Emotional Behavior and the Behavioral Disturbances Produced by Repeated Exposure to Reward Substances.International journal of molecular sciences · 2025Review
- Genetic associations between orexin genes and phenotypes related to behavioral regulation in humans, including substance use.Molecular psychiatry · 2025Article
- Dynorphinergic lateral hypothalamus to posterior ventral tegmental area pathway matures after adolescence in male rats.Neuropharmacology · 2025Article
- Lateral hypothalamus and eating: cell types, molecular identity, anatomy, temporal dynamics and functional roles.Experimental & molecular medicine · 2025Review
100 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine self-administration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.
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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.