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.

Public Health Relevance

Cocaine abuse and addiction remains a significant public health challenge, yet there continues to be a relatively poor understanding of the molecular events that lead to the 'addicted brain'. This application explores the contribution of activin/smad3 signaling cascades in cocaine addiction, and how these pathways regulate drug-induced neural plasticity. The proposed research is relevant to the part of NIH's mission that may identify novel pharmacotherapies to combat psychostimulant addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Wu, Da-Yu
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State University of New York at Buffalo
Schools of Medicine
United States
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Cahill, M E; Walker, D M; Gancarz, A M et al. (2018) The dendritic spine morphogenic effects of repeated cocaine use occur through the regulation of serum response factor signaling. Mol Psychiatry 23:1474-1486
Werner, Craig T; Viswanathan, Rathipriya; Martin, Jennifer A et al. (2018) E3 Ubiquitin-Protein Ligase SMURF1 in the Nucleus Accumbens Mediates Cocaine Seeking. Biol Psychiatry 84:881-892
Martin, Jennifer A; Caccamise, Aaron; Werner, Craig T et al. (2018) A Novel Role for Oligodendrocyte Precursor Cells (OPCs) and Sox10 in Mediating Cellular and Behavioral Responses to Heroin. Neuropsychopharmacology 43:1385-1394
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Wang, Zi-Jun; Martin, Jennifer A; Gancarz, Amy M et al. (2017) Activin A is increased in the nucleus accumbens following a cocaine binge. Sci Rep 7:43658
Damez-Werno, Diane M; Sun, HaoSheng; Scobie, Kimberly N et al. (2016) Histone arginine methylation in cocaine action in the nucleus accumbens. Proc Natl Acad Sci U S A 113:9623-8
Gancarz, Amy; Jouroukhin, Yan; Saito, Atsushi et al. (2016) DISC1 signaling in cocaine addiction: Towards molecular mechanisms of co-morbidity. Neurosci Res 105:70-4
Wang, Zi-Jun; Martin, Jennifer A; Mueller, Lauren E et al. (2016) BRG1 in the Nucleus Accumbens Regulates Cocaine-Seeking Behavior. Biol Psychiatry 80:652-660
Sun, HaoSheng; Martin, Jennifer A; Werner, Craig T et al. (2016) BAZ1B in Nucleus Accumbens Regulates Reward-Related Behaviors in Response to Distinct Emotional Stimuli. J Neurosci 36:3954-61
Cahill, Michael E; Bagot, Rosemary C; Gancarz, Amy M et al. (2016) Bidirectional Synaptic Structural Plasticity after Chronic Cocaine Administration Occurs through Rap1 Small GTPase Signaling. Neuron 89:566-82

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