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Cadherins mediate cocaine-induced synaptic plasticity and behavioral conditioning

Nature Neuroscience volume 20, pages 540549 (2017) | Download Citation

Abstract

Drugs of abuse alter synaptic connections in the reward circuitry of the brain, which leads to long-lasting behavioral changes that underlie addiction. Here we show that cadherin adhesion molecules play a critical role in mediating synaptic plasticity and behavioral changes driven by cocaine. We demonstrate that cadherin is essential for long-term potentiation in the ventral tegmental area and is recruited to the synaptic membranes of excitatory synapses onto dopaminergic neurons following cocaine-mediated behavioral conditioning. Furthermore, we show that stabilization of cadherin at the membrane of these synapses blocks cocaine-induced synaptic plasticity, leading to a reduction in conditioned place preference induced by cocaine. Our findings identify cadherins and associated molecules as targets of interest for understanding pathological plasticity associated with addiction.

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Acknowledgements

We thank the UBC Bioimaging Facility for use of shared equipment for sample processing; S.B. Floresco for extensive discussion and comments on the manuscript; C.A. Winstanley, T.P. O'Connor, K. Haas and D.W. Allan for comments on the manuscript; and K. Goodwin for assistance with data analysis. This work was supported by grants from Canadian Institutes of Health Research MOP-130526 to S.X.B., and MOP-102617 and FDN-147473 to S.L.B.

Author information

Author notes

    • Fergil Mills
    •  & Andrea K Globa

    These authors contributed equally to this work.

Affiliations

  1. Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

    • Fergil Mills
    • , Andrea K Globa
    • , Catherine M Cowan
    • , Mahsan Mobasser
    •  & Shernaz X Bamji
  2. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

    • Shuai Liu
    •  & Stephanie L Borgland
  3. Department of Psychiatry and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

    • Anthony G Phillips

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Contributions

F.M. and A.K.G. performed all behavioral, immunogold electron microscopy, and immunohistochemistry experiments. S.L. performed all electrophysiological experiments under S.L.B.'s supervision. C.M.C. assisted with EM sample processing and immunoelectron microscopy and performed biochemical experiments. M.M. assisted with data analysis and genotyping of mice. A.G.P. provided experimental reagents. F.M., A.K.G. and S.X.B. designed all experiments, interpreted the results and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stephanie L Borgland or Shernaz X Bamji.

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https://doi.org/10.1038/nn.4503

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