Role of Wnt/beta-catenin signaling pathway in cocaine induced sensitization

SANTIAGO CUESTA, ; MARÍA J. SEVERIN, ; JORGELINA BATUECAS,. ; SILVANA B. ROSSO; ALEJANDRA M. PACCHIONI

New Orleans

Congreso; Annual Meeting of the Society for Neuroscience; 2012

Society for Neuroscience

Wnt signaling pathways are essential for development of many tissues and organs, including the mammalian brain. Wnt factors are cistein rich secreted proteins that interact with their receptors: Frizzled, Ryk, and Ror. As a result of the interaction, Dishevelled (DVL) is activated, and consequently, one of three pathways: Wnt/-catenin, Planar Cell Polarity, or Wnt/calcium pathways. These three signaling pathways participate in different events such as cell fate decisions, tissue polarity, cell movement, neurogenesis, neuronal development and function. In the Wnt/-catenin pathway, DVL inhibits GSK-3β which stabilizes -catenin. Recently, it has been shown that Wnt signaling pathways are involved in neuropsychiatric diseases like Alzheimer and schizophrenia. Moreover chronic amphetamine decreased protein levels of GSK-3β and -catenin in dopaminergic neurons while dopaminergic antagonists increased them in dopaminergic neurons and in their projections. Since schizophrenia and cocaine neuroadaptations targeted the mesolimbic system, and cocaine induces changes similar to those observed in mammalian development that could involve the Wnt signaling pathway; our main goal was to elucidate the role of the Wnt signaling pathway in cocaine induced neuroadaptations underlying sensitization. Therefore, we first compared proteins levels of Wnt intracellular effectors in Nucleus Accumbens (NAcc) and in the Prefrontal Cortex (PFC) of cocaine sensitized animals to their controls. Male Wistar rats (300-350g) underwent a cocaine injection scheduled developed by Kalivas et al.. Accordingly, cocaine injections (15 mg/Kg i.p) on Day 1 and Day 7 were given in locomotor activity boxes, and motor activity was recorded for 2 hs. In between, the rats received a total of five daily injections (30 mg/kg i.p.) in their home cages. Animals were sacrificed 3 or 24hs after cocaine injection on Day 7. Our preliminary data show that cocaine differentially changed β-catenin protein levels depending on the brain area studied. Thus, it was decreased in PFC at 3 or 24hs after cocaine injection while no changes were found in NAcc at any time point. This data suggests that Wnt canonical pathway in the PFC is involved in the development of cocaine induced sensitization. To further analyze the role of this pathway in cocaine sensitization we will evaluate the levels of others Wnt effectors (i.e. GSK-3β, DVL, etc) as well as if we can block cocaine sensitization by inhibiting the Wnt/-catenin pathway in the PFC. Furthermore, ongoing studies are evaluating the role of Wnt signaling pathways in the expression of cocaine sensitization.