Involvement of Wnt/βcatenin pathway in cocaine induced sensitization.

S. CUESTA; S.B. ROSSO,; A.M.PACCHIONI

Washington

Congreso; 44nd Annual Meeting of Neurosciences; 2014

Society for Neuroscience

Wnt factors are cistein rich secreted proteins which interact with one of 2 membrane receptors: Frizzled and Ryk. As a result of the interaction Dishevelled (DVL) is activated, and consequently, one of three pathways: canonical or Wnt/βcatenin, Planar Cell Polarity, and Wnt/calcium pathways. These three ways participate in different cell fates decisions like synaptogenesis, cell and tissue polarity and cell movement. Despite all the information about these factors in mammalian brain development, little is known regarding its role in adulthood. In the last years it has been revealed that Wnt pathways are involved in neuropsychiatric diseases. In schizophrenia, antipsychotic and amphetamine treatments lead to opposite changes in Wnt?s effectors. Taking into account that all these evidence involves the dopaminergic pathways, our main goal was to evaluate the role of Wnt pathway in the longlasting neuroadaptations induced by cocaine. According to recent evidence, we started evaluating the Wnt/ βcatenin pathway, where the activation of DVL inhibits GSK3β and lead to the stabilization of βcat. We have already found that development of cocaine induced sensitization after 7 days of cocaine treatment (2x15 mg/kg i.p and 5x30 mg/kg i.p.) is associated with modifications in βcatenin (βcat) levels in prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (DS). Moreover we have also found that a systemic treatment with a nonspecific inhibitor of the Gsk3β blocks the development of cocaine sensitization by restoring βcat´s modifications. Our new data reveals that changes in βcat levels are only present when an animal showed behavioral sensitization after a cocaine treatment. On the other hand, we found that behavioral sensitization is not only related to a reduction in βcat in PFC, DS and Amyg, but also to an increase in Gsk3β activity and a reduction in Axin2mRNA levels (target gene of the pathway) in PFC, suggesting an inhibition of Wnt/βcatenin pathway in this area. Then, we evaluate if these PFC changes were necessary for cocaine sensitization. In order to do that, rats received an intraPFC infusion of Sulindac an hour before cocaine between day 2 and 6 of a 7 i.p. injections, administered once a day, of 15mg/kg of cocaine. The results showed that blocking PFC Wnt/βcatenin pathway with Sulindac, prior to cocaine injections, enhances the development of behavioral sensitization. So far our data suggests that cocaine sensitization is associated with modifications of Wnt/βcatenin pathway, and particularly, with an inhibition in PFC.