Orexin A in the VTA Is Critical for the Induction of Synaptic Plasticity and Behavioral Sensitization to Cocaine
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Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.
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Orexin facilitates LTP induction in VTA and hippocampus, directly and via LC noradrenergic release.
“The wake-promoting neuropeptide orexin robustly facilitated LTP induction in the ventral tegmental area (VTA) and in the hippocampus, directly and via LC noradrenergic release, respectively (115, 1296).”
From About Sleep's Role in Memory (2013) · cites this paper as [115]
The Discussion (page unavailable) reports that orexin A potentiates synaptic responses in VTA dopamine neurons and that blocking its receptor prevents induction of cocaine-associated synaptic potentiation. But the paper describes orexin-induced late-phase LTP as a possibility, rather than establishing that orexin robustly facilitates LTP induction. The hippocampal mechanism appears to belong to the sentence’s other citation, not this one. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe nucleus accumbens shell is part of a neural loop including the lateral hypothalamus and the ventral tegmental area, with orexin neurons playing a key role.
“The nucleus accumbens shell is thereby part of a neural loop including the lateral hypothalamus and the ventral tegmental area, with orexin neurons playing a key role ([7](#B7), [22](#B22), [77](#B77), [98](#B98), [115](#B115), [125](#B125), [175](#B175), [199](#B199)).”
From Food reward, hyperphagia, and obesity (2011) · cites this paper as [22]
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- Authors
- Borgland, S. L., Taha, S. A., Sarti, F., Fields, H. L., & Bonci, A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Bonci, Antonello
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 49
- Issue
- 4
- Pages
- 589-601
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2103848983
- Cited by
- 718
- References
- 66
- Citations by year
- 2026: 13 · 2025: 14 · 2024: 13 · 2023: 22 · 2022: 38 · 2021: 14 · 2020: 25 · 2019: 23 · 2018: 39 · 2017: 37 · 2016: 38 · 2015: 36 · 2014: 41 · 2013: 48 · 2012: 66
- FWCI
- 21.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2723 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Drug Abuse (R01DA015096, 1R01DA15096-01)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- orexin-A, ventral tegmental area, dopaminergic neurons, synaptic plasticity, cocaine sensitization, NMDA receptor potentiation, orexin-1 receptor, addiction, lateral hypothalamus, excitatory synaptic transmission
- MeSH terms
- Orexins, Cyclic AMP, Analysis of Variance, Anesthetics, Local, Animals, Animals, Newborn, Behavior, Animal, Benzoxazoles, Calcium Channel Blockers, Cocaine, Dopamine, Dose-Response Relationship, Drug, Drug Interactions, Electric Stimulation, Enzyme Inhibitors, Immunohistochemistry, Lysine, Male, Motor Activity, Naphthyridines, Neuronal Plasticity, Neurons, Neuropeptides, Protein Kinase C, Quinoxalines, Synapses, Thionucleotides, Time Factors, Tyrosine 3-Monooxygenase, Urea, N-Methylaspartate, Rats, Sprague-Dawley, Ventral Tegmental Area, Patch-Clamp Techniques, Excitatory Amino Acid Agonists, Excitatory Postsynaptic Potentials, Intracellular Signaling Peptides and Proteins, Rats, In Vitro Techniques
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