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

Abstract

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.

Differential Regulation of the Mesoaccumbens Dopamine Circuit by Serotonin2C Receptors in the Ventral Tegmental Area and the Nucleus Accumbens: An In Vivo Microdialysis Study with Cocaine

“…On the other hand, the failure of the intra-VTA injection of SB 242084 to modulate the effects of cocaine on accumbal DA efflux may result from the massive blockade of the 5-HT 2C R in the VTA, which may preclude any possible stimulation of these receptors by cocaine-induced increase in 5-HT levels (Cameron and Williams, 1994). It is noteworthy that DA neurons in the VTA have been recently shown to co-express the protein for the 5-HT 2C R (Bubar and Cunningham, 2006;Ji et al, 2006). By this finding, and considering that the 5-HT 2C R depolarizes cell membranes by inducing phospholipase C-mediated inositol phosphate accumulation and enhancement of intracellular calcium (Stanford et al, 2005), the stimulation of 5-HT 2C Rs located on DA neurons would lead to an excitation of DA neuron activity.…”

The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

“…On the basis of this evidence there have been a number of recent suggestions that the 5-HT 2C receptor might be a valid target for the development of medications for treating drug abuse (Bubar and Cunningham, 2006;Di Giovanni et al, 2006;Higgins and Fletcher, 2003;Ji et al, 2006). In the present experiments, we have explored further the potential utility of a 5-HT 2C receptor agonist for drug abuse.…”

Advances in behavioral genetics: mouse models of autism

“…220 The altered excitation state of cortex in the Tsc1 conditional null mouse is not associated with tuber formation or changes in distribution of GAD67, used as a marker for GABAergic function. 219 The PI3K pathway is antagonized by PTEN, but can be stimulated by glutamate, 221 serotonin 222 and dopamine. 223 BDNF can also stimulate the pathway through TrkB, and induces activation of protein synthesis in neuronal dendrites.…”