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Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine

Nature Neuroscience volume 12, pages 602–610 (2009)Cite this article

Abstract

Plastic changes in glutamatergic synapses that lead to endurance of drug craving and addiction are poorly understood. We examined the turnover and trafficking of NMDA receptors and found that chronic exposure to the psychostimulant amphetamine (AMPH) induced selective downregulation of NMDA receptor NR2B subunits in the confined surface membrane pool of rat striatal neurons at synaptic sites. This downregulation was a long-lived event and was a result of the destabilization of surface-expressed NR2B caused by accelerated ubiquitination and degradation of crucial NR2B-anchoring proteins by the ubiquitin-proteasome system. The biochemical loss of synaptic NR2B further translated to the modulation of synaptic plasticity in the form of long-term depression at cortico-accumbal glutamatergic synapses. Behaviorally, genetic disruption of NR2B induced and restoration of NR2B loss prevented behavioral sensitization to AMPH. Our data identify NR2B as an important regulator in the remodeling of excitatory synapses and persistent psychomotor plasticity in response to AMPH.

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Figure 1: Repeated AMPH administration causes behavioral sensitization and reduces NR2B protein expression in the rat striatum.
Figure 2: Repeated AMPH administration reduces the amount of NR2B protein that is present in specific subcellular compartments.
Figure 3: Repeated AMPH administration reduces NR2B protein levels in the specific surface membrane pool.
Figure 4: Repeated AMPH administration increases ubiquitin conjugation in striatal neurons.
Figure 5: Repeated AMPH administration remodels excitatory synapses via the ubiquitin-proteasome system.
Figure 6: Repeated AMPH administration affects NMDAR-mediated, ifenprodil-sensitive EPSCs and synaptic plasticity at cortico-accumbal glutamatergic synapses.
Figure 7: Effects of RO25-6981 on behavioral responses to acute or chronic AMPH administration.
Figure 8: Effects of NR2B siRNAs on behavioral responses to AMPH.

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Acknowledgements

We thank L.S. Wang and M.-L. Guo for technical support. This work was supported by grants from the US National Institutes of Health (R01DA010355 and R01MH061469 to J.Q.W.), a grant from the Saint Luke's Hospital foundation (J.Q.W.), the 973 Program (No. 2007CB507404, J.-G.C.) and the Chang Jiang Scholar Program of China (J.-G.C).

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  1. Li-Min Mao, Wei Wang and Xiang-Ping Chu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Basic Medical Science, University of Missouri Kansas City, School of Medicine, Kansas City, Missouri, USA

    Li-Min Mao, Xiang-Ping Chu, Guo-Chi Zhang, Xian-Yu Liu, Christopher J Papasian & John Q Wang

  2. Department of Pharmacology and the Key Laboratory of Neurological Diseases of the Ministry of Education of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Wei Wang, Yuan-Jian Yang & Jian-Guo Chen

  3. Department of Anesthesiology, University of Missouri Kansas City, School of Medicine, Kansas City, Missouri, USA

    Michelle Haines, Eugene E Fibuch & John Q Wang

  4. Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA

    Shilpa Buch

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Contributions

L.-M.M., W.W., G.-C.Z., X.-Y.L. and M.H. conducted the biochemical and behavioral experiments and analyzed the data. W.W., X.-P.C. and Y.-J.Y. performed the electrophysiological experiments. C.J.P., E.E.F. and S.B. collaborated by providing expert advice, analyzing and interpreting the data, and developing and editing the manuscript. J.-G.C. oversaw the electrophysiological experiments and other studies and co-wrote the manuscript. J.Q.W. supervised the project, designed the experiments and wrote the manuscript.

Corresponding authors

Correspondence to Jian-Guo Chen or John Q Wang.

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Mao, LM., Wang, W., Chu, XP. et al. Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine. Nat Neurosci 12, 602–610 (2009). https://doi.org/10.1038/nn.2300

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