Nature Medicine
- 12, 324 - 329 (2006)
Published online: 12 February 2006; | doi:10.1038/nm1349
Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuseShao-Ping Ji1, Yun Zhang1, Jamie Van Cleemput1, Wen Jiang1, Mingxia Liao2, 3, Lei Li2, 3, Qi Wan2, 3, Jon R Backstrom4 & Xia Zhang11
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, 103 Wiggins Road, Saskatoon, Saskatchewan, Canada S7N 5E4. 2
Toronto Western Research Institute, University of Toronto, 399 Bathurst Street, Toronto, Canada M5T 2S8. 3
Department of Physiology, University of Toronto, 399 Bathurst Street, Toronto, Canada M5T 2S8. 4
Department of Medicine, Vanderbilt University Medical Center, 21st Avenue South and Garland Avenue, Nashville, Tennessee 37232, USA.
Correspondence should be addressed to Xia Zhang zhangxia@duke.usask.ca 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  9-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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