Cocaine-induced neuroplasticity: a new role for TGF beta signaling

DESCRIPTION (provided by applicant): The proposed studies investigate the role of activin receptor signaling cascades in mediating the long-lasting changes in the brain's reward circuits, which contribute to the complex behavioral abnormalities that comprise an addicted state. To date there is no effective pharmacotherapy for addiction to stimulants, such as cocaine, highlighting the dire need for further understanding of how such drugs of abuse "re-wire" the brain. Neuronal plasticity is considered a neural substrate of the long-term addicted state, but there is a scarcity of mechanistic evidence that explores the molecular mechanism of cocaine-induced structural plasticity. Guided by exciting preliminary data demonstrating that in the Nucleus Accumbens (NAc) of animals of self-administering cocaine, activin receptor expression and signaling is increased, this application will test the following hypotheses: (Aim I) cocaine self-administration regulates the activin receptor-Smad pathway. Consequently, following cocaine self-administration the activin-smad pathway regulates both (a) actin dynamics and (b) Smad gene targets; (Aim II) Activin-Smad pathways are key molecular mechanisms underlying cocaine-induced dendritic spine plasticity of NAc neurons following cocaine self-administration; (Aim III) Activin receptor and Smad signaling pathways directly mediate cocaine seeking and craving as measured by reinstatement behaviors. This application presents an opportunity to determine, for the first time, the causal role for TGFBeta/activin-smad signaling cascades in facilitating drug seeking behaviors by examining cocaine-induced plasticity on cellular (i.e. structural) and behavioral levels (i.e. reinstatement). The findings from the work in this application will elucidate mechanisms by which chronic cocaine exposure induces long-term changes in plasticity of NAc neurons, and provides new directions for the development of novel therapies for cocaine addiction.