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Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse

Nature Medicine volume 12, pages 324–329 (2006)Cite this article

Abstract

The widespread distribution of the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the adult brain1 suggests its role in a broad range of brain functions. Here we show evidence supporting a physical interaction of PTEN with a region in the third intracellular loop (3L4F) of the serotonin 5-HT2C receptor (5-HT2cR, formerly 5-HT1c receptor2) in cell cultures. PTEN limits agonist-induced phosphorylation of 5-HT2cR through its protein phosphatase activity. We showed the probable existence of PTEN:5-HT2cR complexes in putative dopaminergic neurons in the rat ventral tegmental area (VTA), a brain region in which virtually all abused drugs exert rewarding effects by activating its dopamine neurons3,4. We synthesized the interfering peptide Tat-3L4F, which is able to disrupt PTEN coupling with 5-HT2cR. Systemic application of Tat-3L4F or the 5-HT2cR agonist Ro600175 suppressed the increased firing rate of VTA dopaminergic neurons induced by Δ9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana. Using behavioral tests, we found that Tat-3L4F or Ro600175 blocks conditioned place preference of THC or nicotine, and that Ro600175, but not Tat-3L4F, produces anxiogenic effects, penile erection, hypophagia and motor functional suppression. These results suggest a potential strategy for treating drug addiction with the Tat-3L4F peptide.

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Figure 1: Interaction of PTEN with 5-HT2cR in PC12 cells.
Figure 2: Interaction and coexpression of PTEN and 5-HT2cR in the rat VTA.
Figure 3: Modulation of the firing rate of VTA dopamine neurons by Ro600175 (Ro), SB242084 (SB), Tat-3L4F (3L4F) and Tat-3L5F (3L5F).
Figure 4: Behavioral effects of Tat-3L4F (3L4F, 0.1 μmol/kg), Tat-3L5F (3L5F, 0.1 μmol/kg) and Ro600175 (Ro, 3 mg/kg).

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Acknowledgements

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada awarded to X.Z., who is the recipient of the CIHR New Investigator Award. S.-P.J. and W.J. were supported by Postdoctoral Fellowship Awards from the Saskatchewan Health Research Foundation, Canada. We thank Y. Li and G. Kort for technical assistance and X. Wu for confocal imaging. G129R and G129E were provided by F. Furnari at the Ludwig Institute for Cancer Research, University of California at San Diego. We also thank M. Tamura at the US National Institutes of Health for providing wild-type PTEN.

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Authors and Affiliations

  1. Department of Psychiatry, Neuropsychiatry Research Unit, University of Saskatchewan, 103 Wiggins Road, Saskatoon, S7N 5E4, Saskatchewan, Canada

    Shao-Ping Ji, Yun Zhang, Jamie Van Cleemput, Wen Jiang & Xia Zhang

  2. Toronto Western Research Institute, University of Toronto, 399 Bathurst Street, Toronto, M5T 2S8, Canada

    Mingxia Liao, Lei Li & Qi Wan

  3. Department of Physiology, University of Toronto, 399 Bathurst Street, Toronto, M5T 2S8, Canada

    Mingxia Liao, Lei Li & Qi Wan

  4. Department of Medicine, Vanderbilt University Medical Center, 21st Avenue South and Garland Avenue, Nashville, 37232, Tennessee, USA

    Jon R Backstrom

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Ji, SP., Zhang, Y., Van Cleemput, J. et al. Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. Nat Med 12, 324–329 (2006). https://doi.org/10.1038/nm1349

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