QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, August 16, 2006, 26(33):8549-8558; doi:10.1523/JNEUROSCI.5179-05.2006

This Article Full Text Full Text (PDF) An erratum has been published Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (38) Citing Articles via Google Scholar Google Scholar Articles by Schilström, B. Articles by Bonci, A. Search for Related Content PubMed PubMed Citation Articles by Schilström, B. Articles by Bonci, A.

 Previous Article  |  Next Article 

Cellular/Molecular
Cocaine Enhances NMDA Receptor-Mediated Currents in Ventral Tegmental Area Cells via Dopamine D₅ Receptor-Dependent Redistribution of NMDA Receptors

Björn Schilström,^2 * Rami Yaka,^3 * Emanuela Argilli,^1 * Neesha Suvarna,¹ Johanna Schumann,³ Billy T. Chen,¹ Melissa Carman,¹ Vineeta Singh,¹ William S. Mailliard,¹ Dorit Ron,¹ and Antonello Bonci

¹Ernest Gallo Clinic and Research Center and Department of Neurology, University of California, San Francisco, San Francisco, California 94110, ²Section of Neuropsychopharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, S-171 77 Stockholm, Sweden, and ³Department of Pharmacology, School of Pharmacy, Hebrew University, Jerusalem 91120, Israel

Correspondence should be addressed to Dr. Antonello Bonci, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: bonci{at}itsa.ucsf.edu

Cocaine-induced plasticity of glutamatergic synaptic transmission in the ventral tegmental area (VTA) plays an important role in brain adaptations that promote addictive behaviors. However, the mechanisms responsible for triggering these synaptic changes are unknown. Here, we examined the effects of acute cocaine application on glutamatergic synaptic transmission in rat midbrain slices. Cocaine caused a delayed increase in NMDA receptor (NMDAR)-mediated synaptic currents in putative VTA dopamine (DA) cells. This effect was mimicked by a specific DA reuptake inhibitor and by a DA D₁/D₅ receptor agonist. The effect of cocaine was blocked by a DA D₁/D₅ receptor antagonist as well as by inhibitors of the cAMP/cAMP-dependent protein kinase A (PKA) pathway. Furthermore, biochemical analysis showed an increase in the immunoreactivity of the NMDAR subunits NR1 and NR2B and their redistribution to the synaptic membranes in VTA neurons. Accordingly, NMDAR-mediated EPSC decay time kinetics were significantly slower after cocaine, suggesting an increased number of NR2B-containing NMDARs. Finally, pharmacological analysis indicates that NR2B subunits might be incorporated in triheteromeric NR1/NR2A/NR2B complexes rather than in "pure" NR1/NR2B NMDA receptors. Together, our data suggest that acute cocaine increases NMDAR function in the VTA via activation of the cAMP/PKA pathway mediated by a DA D₅-like receptor, leading to the insertion of NR2B-containing NMDARs in the membrane. These results provide a potential mechanism by which acute cocaine promotes synaptic plasticity of VTA neurons, which could ultimately lead to the development of addictive behaviors.

Key words: synaptic transmission; receptor trafficking; addiction; NMDAR; dopamine; cocaine

---

Received Sept. 30, 2005; revised June 29, 2006; accepted July 16, 2006.

Correspondence should be addressed to Dr. Antonello Bonci, Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608. Email: bonci{at}itsa.ucsf.edu

This article has been cited by other articles:

				T.-X. Xu, T. D. Sotnikova, C. Liang, J. Zhang, J. U. Jung, R. D. Spealman, R. R. Gainetdinov, and W.-D. Yao Hyperdopaminergic Tone Erodes Prefrontal Long-Term Potential via a D2 Receptor-Operated Protein Phosphatase Gate J. Neurosci., November 11, 2009; 29(45): 14086 - 14099. [Abstract] [Full Text] [PDF]

				M. Heshmati Cocaine-Induced LTP in the Ventral Tegmental Area: New Insights Into Mechanism and Time Course Illuminate the Cellular Substrates of Addiction J Neurophysiol, June 1, 2009; 101(6): 2735 - 2737. [Abstract] [Full Text] [PDF]

				J. Schumann and R. Yaka Prolonged Withdrawal from Repeated Noncontingent Cocaine Exposure Increases NMDA Receptor Expression and ERK Activity in the Nucleus Accumbens J. Neurosci., May 27, 2009; 29(21): 6955 - 6963. [Abstract] [Full Text] [PDF]

				K. E. Stephan, K. J. Friston, and C. D. Frith Dysconnection in Schizophrenia: From Abnormal Synaptic Plasticity to Failures of Self-monitoring Schizophr Bull, May 1, 2009; 35(3): 509 - 527. [Abstract] [Full Text] [PDF]

				J. A. Varela, S. J. Hirsch, D. Chapman, L. S. Leverich, and R. W. Greene D1/D5 Modulation of Synaptic NMDA Receptor Currents J. Neurosci., March 11, 2009; 29(10): 3109 - 3119. [Abstract] [Full Text] [PDF]

				L. A. Sombers, M. Beyene, R. M. Carelli, and R. Mark Wightman Synaptic Overflow of Dopamine in the Nucleus Accumbens Arises from Neuronal Activity in the Ventral Tegmental Area J. Neurosci., February 11, 2009; 29(6): 1735 - 1742. [Abstract] [Full Text] [PDF]

				E. Argilli, D. R. Sibley, R. C. Malenka, P. M. England, and A. Bonci Mechanism and Time Course of Cocaine-Induced Long-Term Potentiation in the Ventral Tegmental Area J. Neurosci., September 10, 2008; 28(37): 9092 - 9100. [Abstract] [Full Text] [PDF]

				C. Gao and M. E. Wolf Dopamine Alters AMPA Receptor Synaptic Expression and Subunit Composition in Dopamine Neurons of the Ventral Tegmental Area Cultured with Prefrontal Cortex Neurons J. Neurosci., December 26, 2007; 27(52): 14275 - 14285. [Abstract] [Full Text] [PDF]

				S. I. Cohen-Matsliah, I. Brosh, K. Rosenblum, and E. Barkai A Novel Role for Extracellular Signal-Regulated Kinase in Maintaining Long-Term Memory-Relevant Excitability Changes J. Neurosci., November 14, 2007; 27(46): 12584 - 12589. [Abstract] [Full Text] [PDF]

				S. Kourrich, P. E. Rothwell, J. R. Klug, and M. J. Thomas Cocaine Experience Controls Bidirectional Synaptic Plasticity in the Nucleus Accumbens J. Neurosci., July 25, 2007; 27(30): 7921 - 7928. [Abstract] [Full Text] [PDF]

				C. Xiao, C. Zhou, K. Li, and J.-H. Ye Presynaptic GABAA receptors facilitate GABAergic transmission to dopaminergic neurons in the ventral tegmental area of young rats J. Physiol., May 1, 2007; 580(3): 731 - 743. [Abstract] [Full Text] [PDF]

				S. N. Blythe, J. F. Atherton, and M. D. Bevan Synaptic Activation of Dendritic AMPA and NMDA Receptors Generates Transient High-Frequency Firing in Substantia Nigra Dopamine Neurons In Vitro J Neurophysiol, April 1, 2007; 97(4): 2837 - 2850. [Abstract] [Full Text] [PDF]

				J. Wang, S. Carnicella, K. Phamluong, J. Jeanblanc, J. A. Ronesi, N. Chaudhri, P. H. Janak, D. M. Lovinger, and D. Ron Ethanol Induces Long-Term Facilitation of NR2B-NMDA Receptor Activity in the Dorsal Striatum: Implications for Alcohol Drinking Behavior J. Neurosci., March 28, 2007; 27(13): 3593 - 3602. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help