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

Nat Med. 2006 Mar;12(3):324-9. doi: 10.1038/nm1349. Epub 2006 Feb 12.


The widespread distribution of the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) in the adult brain 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 receptor) 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 neurons. 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 delta9-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Addictive / chemically induced
  • Behavior, Addictive / metabolism*
  • Dopamine / metabolism
  • Illicit Drugs / pharmacology*
  • Neurons / metabolism
  • PC12 Cells
  • PTEN Phosphohydrolase / antagonists & inhibitors*
  • PTEN Phosphohydrolase / metabolism*
  • Protein Binding
  • Rats
  • Receptor, Serotonin, 5-HT2C / chemistry
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Recombinant Fusion Proteins
  • Serotonin 5-HT2 Receptor Antagonists*
  • Substance-Related Disorders / metabolism*
  • Ventral Tegmental Area / cytology


  • Illicit Drugs
  • Receptor, Serotonin, 5-HT2C
  • Recombinant Fusion Proteins
  • Serotonin 5-HT2 Receptor Antagonists
  • Tat-3L4F peptide
  • PTEN Phosphohydrolase
  • Pten protein, rat
  • Dopamine