PTEN-5-HT2C coupling: a new target for treating drug addiction.

It is well known that the ventral tegmental area (VTA) is a brain region in which virtually all abused drugs exert rewarding effects by activating its dopamine neurons. We recently found that the tumour suppressor enzyme phosphatase and tensin homologue deleted on chromosome 10 (PTEN) directly interacts to a region in the third intracellular loop (3L4F) of serotonin 5-HT2C receptors (5-HT2cR) in the rat VTA. PTEN limits agonist-induced 5-HT2cR phosphorylation via its protein phosphatase activity. Systemic or intra-amygdaloid application of the interfering peptide Tat-3L4F is able to disrupt PTEN coupling with 5-HT2cR in the rat VTA, resulting both in a suppression of the increased firing rate of VTA dopaminergic neurons induced by Delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, and in a blockade of the conditioned place preference induced by THC and nicotine [Ji, S.P. et al. (2006). Nat. Med., 12: 324-329]. Because the blockade effects of Tat-3L4F peptide on the conditioned preference could be achieved by the suppression of Tat-3L4F peptide on the rewarding and/or learning/memory mechanisms associated with conditioned place preference, we recently explored whether Tat-3L4F can affect learning and memory. We observed that Tat-3L4F did not produce significant effects on spatial learning and memory in a Morris water maze test, thus indicating that Tat-3L4F can effectively suppress the rewarding effects induced by drugs of abuse.