Ji Shao-Ping, Zhang Yun, Van Cleemput Jamie, Jiang Wen, Liao Mingxia, Li Lei, Wan Qi, Backstrom Jon R, Zhang Xia
Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, 103 Wiggins Road, Saskatoon, Saskatchewan, Canada S7N 5E4.
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.
肿瘤抑制因子PTEN（第10号染色体缺失的磷酸酶和张力蛋白同源物）在成人大脑中广泛分布，这表明它在多种脑功能中发挥作用。在此，我们展示了在细胞培养中支持PTEN与5-羟色胺5-HT2C受体（5-HT2cR，原称5-HT1c受体）第三个细胞内环（3L4F）区域发生物理相互作用的证据。PTEN通过其蛋白磷酸酶活性限制激动剂诱导的5-HT2cR磷酸化。我们发现大鼠腹侧被盖区（VTA）的假定多巴胺能神经元中可能存在PTEN:5-HT2cR复合物，几乎所有滥用药物都通过激活该脑区的多巴胺能神经元产生奖赏效应。我们合成了干扰肽Tat-3L4F，它能够破坏PTEN与5-HT2cR的偶联。全身应用Tat-3L4F或5-HT2cR激动剂Ro600175可抑制δ9-四氢大麻酚（THC，大麻的精神活性成分）诱导的VTA多巴胺能神经元放电频率增加。通过行为测试，我们发现Tat-3L4F或Ro600175可阻断THC或尼古丁的条件性位置偏爱，并且Ro600175而非Tat-3L4F会产生致焦虑效应、阴茎勃起、食欲减退和运动功能抑制。这些结果提示了一种用Tat-3L4F肽治疗药物成瘾的潜在策略。
