Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse.
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.
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, 103 Wiggins Road, Saskatoon, Saskatchewan, Canada S7N 5E4.
Shao-Ping
SP
Ji
Yun
Y
Zhang
Jamie
J
Van Cleemput
Wen
W
Jiang
Mingxia
M
Liao
Lei
L
Li
Qi
Q
Wan
Jon R
JR
Backstrom
Xia
X
Zhang
D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D013287:Illicit Drugs / Q000494:pharmacology*; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D058830:Serotonin 5-HT2 Receptor Antagonists; D019966:Substance-Related Disorders / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000166:cytology
D013287:Illicit Drugs; D044405:Receptor, Serotonin, 5-HT2C; D011993:Recombinant Fusion Proteins; D058830:Serotonin 5-HT2 Receptor Antagonists; C532629:Tat-3L4F peptide; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat; D004298:Dopamine