Involvement of Wnt/b-catenin pathway in cocaine induced sensitization

CUESTA, SANTIAGO; ROSSO, SILVANA B; PACCHIONI, ALEJANDRA M

,Washington, DC, USA

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/b-catenin,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 long-lasting neuroadaptations induced by cocaine. According to recent evidence, we started evaluating the Wnt/b-catenin pathway, where the activation of DVL inhibits GSK3β and lead to the tabilization of b-cat. We have already found that development of cocaine induced sensitization after 7 days of cocaine treatment (2x15mg/kg i.p and 5x30 mg/kg i.p.) is associated with modifications in b-catenin (bcat) levels in prefrontal cortex (PFC), amygdala (Amyg) and dorsal striatum (DS). Moreover we have also found that a systemic treatment with a non-specific inhibitor of the Gsk3b blocks the development of cocaine sensitization by restoring bcat´s modifications. Our new data reveals that changes in b-catenin 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 bcat in PFC, DS and Amyg, but also to an increase in Gsk3b activity and a reduction in Axin2 mRNA levels (target gene of the pathway) in PFC, suggesting an inhibition of Wnt/b-catenin pathway in this area. Then, we evaluate if these PFC changes were necessary for cocaine sensitization. In order to do that, rats received an intra-PFC 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/b-catenin 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/b-catenin pathway, and particularly, with an inhibition in PFC.