Disruption of PTEN Coupling to 5HT2C Receptor Reduces VTA Dopamine Activity

While phosphorylation of 5-HT2C receptor blocks its desensitization, enhances its resensitization, and is necessary for efficient signaling (Backstrom et al. 2000; Muller and Carey 2006), direct protein-protein coupling between PTEN and 5-HT2C receptor provides PTEN with the capacity to dephosphorylate 5-HT2C receptor. PTEN may therefore be able to regulate the function of 5-HT2C receptor, which could be blocked by Tat-3L4F-mediated disruption of PTEN coupling with 5-HT2C receptor. Previous research has demonstrated that the activity or firing rate of VTA dopamine neurons innervating the NAc was increased by blockade of the 5-HT2C receptor and decreased by activation of the 5-HT2C receptor (Di Matteo et al. 2002; Higgins and Fletcher 2003). To determine whether PTEN can regulate the firing rate of VTA dopamine neurons through its interaction with 5-HT2C receptor, we conducted in vivo recording of the activity of VTA dopamine neurons directly innervating the NAc. We first confirmed that selective 5-HT2C receptor antagonist and agonist decreased and increased the firing rate of VTA dopamine neurons, respectively (Ji et al. 2006), thereby supporting the previous findings that VTA dopamine neurons are tonically inhibited by 5-HT2C receptor. Since drug reward is associated with increased firing of VTA dopamine neurons resulting in elevated levels of dopamine in the NAc, controlling the firing rate through the action of the 5-HT2C receptor holds great therapeutic potential. Because PTEN interacts with 5-HT2C receptor by dephosphorylating the phosphorylation induced by the 5-HT2C receptor agonist R0600175, disrupting this coupling may inhibit the firing rate of the VTA dopamine neurons by maintaining the activation of 5-HT2C receptor. In agreement with this hypothesis, both a systemic and an intra-VTA injection of Tat-4L4F interfering peptide significantly diminished the firing rate of VTA dopamine neurons, which was effectively reversed by the 5-HT2C antagonist SB 242084 (Ji et al. 2006). These results suggest that disruption of the interaction between PTEN and 5-HT2C receptor using Tat-3L4F can inhibit the VTA dopamine neurons and reduce dopamine release in the NAc.

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Defeat Drugs and Live Free

Being addicted to drugs is a complicated matter condition that's been specified as a disorder that evidences in the obsessional thinking about and utilization of drugs. It's a matter that might continue to get worse and become disastrous and deadly if left untreated.

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