Corticotropin-Releasing Factor Requires CRF Binding Protein to Potentiate NMDA Receptors via CRF Receptor 2 in Dopamine Neurons
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Stress increases addictive behaviors and is a common cause of relapse. Corticotropin-releasing factor (CRF) plays a key role in the modulation of drug taking by stress. However, the mechanism by which CRF modulates neuronal activity in circuits involved in drug addiction is poorly understood. Here we show that CRF induces a potentiation of NMDAR (N-methyl-D-aspartate receptor)-mediated synaptic transmission in dopamine neurons of the ventral tegmental area (VTA). This effect involves CRF receptor 2 (CRF-R2) and activation of the phospholipase C (PLC)-protein kinase C (PKC) pathway. We also find that this potentiation requires CRF binding protein (CRF-BP). Accordingly, CRF-like peptides, which do not bind the CRF-BP with high affinity, do not potentiate NMDARs. These results provide evidence of the first specific roles for CRF-R2 and CRF-BP in the modulation of neuronal activity and suggest that NMDARs in the VTA may be a target for both drugs of abuse and stress.
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Stress causes CRF release into the VTA and NAC shell, and this CRF acts on CRF receptors to induce reinstatement of drug seeking.
“Using stress-induced reinstatement of drug seeking, it has been demonstrated that stress causes CRF release into the VTA and NAC shell (Wang et al 2005; Chen et al 2012a), and this CRF release acts on CRF receptors to induce reinstatement (Ungless et al 2003; Wang et al 2005; Wang et al 2007; Blacktop et al 2011).”
From The behavioral, anatomical and pharmacological parallels between social attachment, love and addiction (2012) · cites this paper as Ungless et al 2003
Cites
Vaughan, J. M., Donaldson, C. J., Bittencourt, J. C., Perrin, M. H., Lewis, K., Sutton, S. W., Chan, R. K. W., Turnbull, A. V., Lovejoy, D. A., RIVIER, C. L., et al. (1995) · Nature · doi:10.1038/378287a0 · Cited by 1,479 · see citing works
Drugs of Abuse and Stress Trigger a Common Synaptic Adaptation in Dopamine Neurons
Saal, D., Dong, Y., Bonci, A., & Malenka, R. C. (2003) · Neuron · doi:10.1016/s0896-6273(03)00021-7 · Cited by 1,147 · see citing works
Self-citationSingle cocaine exposure in vivo induces long-term potentiation in dopamine neurons
Ungless, M. A., Whistler, J. L., Malenka, R. C., & Bonci, A. (2001) · Nature · doi:10.1038/35079077 · Cited by 1,106 · see citing works
Self-citationThe Time Course of Glutamate in the Synaptic Cleft
Clements, J. D., Lester, R. A. J., Tong, G., Jahr, C. E., & Westbrook, G. L. (1992) · Science · doi:10.1126/science.1359647 · Cited by 1,089 · see citing works
The dopamine hypothesis of reward: past and current status
Spanagel, R., & Weiss, F. (1999) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01447-2 · Cited by 967 · see citing works
Reyes, T. M., Lewis, K., Perrin, M. H., Kunitake, K. S., Vaughan, J., Arias, C. A., Hogenesch, J. B., Gulyas, J., Rivier, J., Vale, W. W., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051626398 · Cited by 887 · see citing works
Lovenberg, T. W., Liaw, C. W., Grigoriadis, D. E., Clevenger, W., Chalmers, D. T., Souza, E. B. D., & Oltersdorf, T. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.3.836 · Cited by 846 · see citing works
Stress-induced relapse to heroin and cocaine seeking in rats: a review
Shaham, Y., Erb, S. M., & Stewart, J. (2000) · Brain Research Reviews · doi:10.1016/s0165-0173(00)00024-2 · Cited by 703 · see citing works
Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus
Valentino, R. J., Foote, S. L., & Aston‐Jones, G. (1983) · Brain Research · doi:10.1016/0006-8993(83)90615-7 · Cited by 603 · see citing works
The CRF peptide family and their receptors: yet more partners discovered
Dautzenberg, F. M., & Hauger, R. L. (2002) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(02)01946-6 · Cited by 534 · see citing works
A role for corticotropin releasing factor and urocortin in behavioral responses to stressors
Koob, G. F., & Heinrichs, S. C. (1999) · Brain Research · doi:10.1016/s0006-8993(99)01991-5 · Cited by 530 · see citing works
Burst firing in midbrain dopaminergic neurons
Overton, P. G., & Clark, D. (1997) · Brain Research Reviews · doi:10.1016/s0165-0173(97)00039-8 · Cited by 466 · see citing works
Fitzgerald, L., Ortiz, J., Hamedani, A., & Nestler, E. J. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-01-00274.1996 · Cited by 450 · see citing works
Neuhoff, H., Neu, A. D., Liss, B., & Roeper, J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-04-01290.2002 · Cited by 400 · see citing works
Schulz, D. W., Mansbach, R. S., Sprouse, J. S., Braselton, J. P., Collins, J. L., Corman, M. L., Dunaiskis, A. R., Faraci, S., Schmidt, A. W., Seeger, T., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.19.10477 · Cited by 377 · see citing works
Bonci, A., & Malenka, R. C. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-10-03723.1999 · Cited by 318 · see citing works
Self-citationAldenhoff, J. B., Gruol, D. L., Rivier, J., Vale, W., & Siggins, G. R. (1983) · Science · doi:10.1126/science.6603658 · Cited by 309 · see citing works
Georges, F. E., & Aston‐Jones, G. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-12-05173.2002 · Cited by 287 · see citing works
Potter, E., Behan, D. P., Linton, E. A., Lowry, P. J., Sawchenko, P. E., & Vale, W. W. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.9.4192 · Cited by 285 · see citing works
Behan, D., Heinrichs, S., Troncoso, J., Liu, X.-J., Kawas, C., Ling, N., & de Souza, E. D. (1995) · Nature · doi:10.1038/378284a0 · Cited by 248 · see citing works
Enhanced and Delayed Stress-Induced Alcohol Drinking in Mice Lacking Functional CRH1 Receptors
Sillaber, I., Rammes, G., Zimmermann, S., Mahal, B., Zieglgänsberger, W., Wurst, W., Holsboer, F., & Spanagel, R. (2002) · Science · doi:10.1126/science.1069836 · Cited by 220 · see citing works
Blank, T., Nijholt, I. M., Eckart, K., & Spiess, J. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03788.2002 · Cited by 210 · see citing works
Dunn, A. J., & Berridge, C. W. (1987) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(87)90195-x · Cited by 187 · see citing works
Rühmann, A., Bonk, I., Lin, C. R., Rosenfeld, M. G., & Spiess, J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.26.15264 · Cited by 170 · see citing works
Linton, E. A., Behan, D. P., Saphier, P. W., & Lowry, P. J. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-70-6-1574 · Cited by 114 · see citing works
The corticotrophin-releasing factor-binding protein: an act of several parts
Kemp, C. F., Woods, R. J., & Lowry, P. J. (1998) · Peptides · doi:10.1016/s0196-9781(98)00057-6 · Cited by 85 · see citing works
Karchewski, L. A., Kim, F. A., Johnston, J. M., McKnight, R. M., & Verge, V. M. K. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19991018)413:2 · Cited by 81 · see citing works
Heinrichs, S. C., Lapsansky, J., Behan, D. P., Chan, R. K. W., Sawchenko, P. E., Lorang, M. T., LING, N. C., Vale, W., & Souza, E. B. D. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.26.15475 · Cited by 76 · see citing works
Chan, R. K. W., Vale, W. W., & Sawchenko, P. E. (2000) · Neuroscience · doi:10.1016/s0306-4522(00)00322-5 · Cited by 63 · see citing works
Morrow, B. A., Clark, W. A., & Roth, R. H. (1993) · European Journal of Pharmacology · doi:10.1016/0014-2999(93)90855-c · Cited by 57 · see citing works
The binding protein of corticotropin-releasing factor: Ligand-binding site and subunit structure
Jahn, O., Eckart, K., Brauns, O., Tezval, H., & Spiess, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.192449299 · Cited by 52 · see citing works
Heinrichs, S. C., & Joppa, M. A. (2001) · Behavioural Brain Research · doi:10.1016/s0166-4328(01)00174-7 · Cited by 29 · see citing works
Austin, M. C. (1997) · Neuropsychopharmacology · doi:10.1016/s0893-133x(97)00083-3 · Cited by 27 · see citing works
Lowry, P. J., Koerber, S. C., Woods, R. J., et al. (1996) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0160039 · Cited by 15 · see citing works
Action of Three Ectopeptidases on Corticotropin-Releasing Factor: Metabolism and Functional Aspects
Ritchie, J., Davis, T. P., & Nemeroff, C. B. (2002) · Neuropsychopharmacology · doi:10.1038/sj.npp.1300014 · Cited by 13 · see citing works
Distribution of mRNAs encoding CRF receptors in brain and pituitary of rat and mouse
Van Pett, K., Viau, V., Bittencourt, J. C., Chan, R. K. W., Li, H.-Y., Arias, C., Prins, G. S., Perrin, M., Vale, W., & Sawchenko, P. E. (2000) · The Journal of Comparative Neurology · doi:10.1002/1096-9861(20001211)428:2
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Sinha, R. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1441.030 · Cited by 1,904 · see citing works
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Lüscher, C., & Malenka, R. C. (2011) · Neuron · doi:10.1016/j.neuron.2011.01.017 · Cited by 1,105 · see citing works
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Wang, B., Shaham, Y., Zitzman, D., Azari, S., Wise, R. A., & You, Z.-B. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.0955-05.2005 · Cited by 369 · see citing works
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Self-citation
- Authors
- Ungless, M. A., Singh, V., Crowder, T. L., Yaka, R., Ron, D., & Bonci, A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Bonci, Antonello
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2003-07
- Volume
- 39
- Issue
- 3
- Pages
- 401-407
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2070065061
- Cited by
- 297
- References
- 36
- Citations by year
- 2025: 8 · 2024: 6 · 2023: 6 · 2022: 15 · 2021: 4 · 2020: 10 · 2019: 7 · 2018: 18 · 2017: 13 · 2016: 17 · 2015: 18 · 2014: 13 · 2013: 18 · 2012: 17
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (K23 NS42072, K23NS042072)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- corticotropin-releasing factor, CRF-binding protein, CRF receptor 2, NMDA receptor potentiation, dopaminergic neurons, ventral tegmental area, phospholipase C, protein kinase C, stress, drug addiction, synaptic transmission
- MeSH terms
- Animals, Carrier Proteins, Corticotropin-Releasing Hormone, Dopamine, Male, Mice, Inbred C57BL, Neurons, Receptors, N-Methyl-D-Aspartate, Receptors, Corticotropin-Releasing Hormone, Patch-Clamp Techniques, Mice, In Vitro Techniques
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