Tat-3L4F: A Novel Peptide for Treating Drug Addiction by Disrupting Interaction Between PTEN and 5-HT_2C Receptor

Abstract

Compelling evidence has shown that the 5-HT_2C receptor might be a key target for treating drug addiction. While activation of the midbrain ventral tegmental area (VTA) dopamine neurons results in the rewarding effects common to all drugs of abuse, 5-HT_2C agonists instead produce inhibition of these neurons. We recently discovered that the tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) directly interacts with the third intracellular loop (3L4F) of the serotonin 5-HT_2C receptor in VTA dopamine neurons. PTEN counteracts agonist-induced phosphorylation of 5-HT_2C receptors and, thereby, their inactivation through its protein phosphatase activity. Moreover, we have shown that the interfering peptide Tat-3L4F effectively disrupts the protein–protein interaction between PTEN and 5-HT_2C, suppresses the enhanced firing rate of VTA dopamine neurons induced by Δ9-tetrahydrocannabinol (THC), the psychoactive component of marijuana, and blocks the conditioned place preference (CPP) of THC and nicotine. Since CPP tests rely heavily on learning and memory capability, the blocking effects of Tat-3L4F on CPP may be achieved by suppressing learning and memory. Our further experiments suggest that this is unlikely. Thus, Tat-3L4F may present a potentially safer strategy for treating drug abuse.