Advisor: Robert Levenson, PhD
Graduate Program: Pharmacology
Thesis: Applying a Candidate Gene Approach to Investigate the Molecular Changes that Accompany the Development of Addiction-like Behaviors to Opioids in Rats
Research Interest: Role of GPCR interacting proteins in drug addiction
Opioid addiction is a devastating chronic disorder characterized by compulsive drug seeking and a loss of control over drug use. Activation of the mu-opioid receptor (MOR) is critical for mediating the rewarding and addictive properties of opioids. Recent research suggests that MOR signaling is modulated by proteins that interact with MOR to form multiprotein signalplexes. The goal of my thesis research is to understand how MOR interacting proteins contribute to the molecular adaptations induced by opioid exposure and addiction. To achieve this goal, I developed a rodent model for "addiction-like" behaviors for heroin that serves as a platform for investigating potential underlying neural substrates involved in the development of opioid addiction. My central hypothesis is that the transition from opioid use to opioid addiction is accompanied by differential regulation of MOR interacting proteins.
To gain an understanding of the molecular changes that accompany the development of behavioral criteria for "addiction-like" behavior, I analyzed the protein expression of known MOR interacting proteins and the D2 dopamine receptor. Western blotting was used to assess protein expression in the prefrontal cortex, hippocampus, and nucleus accumbens from 14 rats from the heroin self-administration study. I found a differential expression of the D2 dopamine receptor, spinophilin, and wntless that correlated with behavioral evidence of "addiction-like behaviors." These changes in protein expression may reflect molecular correlates of the development of opioid addiction.
This research applies a novel model of "addiction- like" behavior in rats self-administering heroin to analyze the expression of MOR interacting proteins in key brain regions that mediate reward and addiction. My data suggests that spinophilin and wntless are potential molecular substrates that accompany the transition from opioid exposure to opioid addiction. Future research is needed to demonstrate a cause and effect relationship between the expression of MOR interacting proteins and "addiction-like" behaviors. To test whether wntless or spinophilin are important neural substrates for opioid addiction, experiments can be designed to determine if the development of "addiction-like" behaviors can be prevented by blocking the interaction of the MOR with wntless or spinophilin. Further studies are also required to test my working hypothesis that VAPA is involved in the intracellular trafficking of MOR along the vesicular pathway and that this process is altered in the presence of chronic opioid agonist. Understanding the role of VAPA in MOR translocation to the cell surface will provide insight into additional mechanisms of receptor regulation.
43rd Annual Meeting of the American Soc. for Cell Biology, San Francisco, CA
Society for Neuroscience: Drug Reinforcement, Seeking and Reinstatement, San Diego, CA
NIDA Informatics for Data and Resource Discovery in Addiction Research, NIH Neuroscience Center, Rockville, MD
Cellular Biology of Addiction Workshop, Cold Spring Harbor Laboratory, New York, NY
Penn State Neuroscience Institute Mini-Symposium, University Park, PA
Tacelosky, D.M., Alexander, D.N., Morse, M., Hajnal, A., Berg, A., Levenson, R., and Grigson, P.S. (2015). Low Expression of D2R and Wntless Correlates with High Motivation for Heroin. Behavioral Neuroscience, In Press.
McNeil EL, Tacelosky D, Basciano P, Biallas B, Williams R, Damiani P, Deacon S, Fox C, Stewart B, Petruzzi N, Osborn C, Klinger K, Sellers JR, King Smith C, (2004) Actin-dependent motility of melanosomes from fish retinal pigment epithelial cells investigated using in vitro motility assays Cell Motility & the Cytoskeleton 58(2):71-82 PMCID: PMC15083529
Dluzen D, Li G, Tacelosky D, Moreau M, Liu DX (2011) Bcl-2 is a downstream target of ATF5 that mediates ATF5' pro-survival function in a cell type-dependent manner JBC 286(9):7705-13 PMCID: PMC3045024
Woll MP, De Cotiis Da, Bewley MC,Tacelosky DM, Levenson R, Flanagan JM (2011) Interaction between the D2 Dopamine Receptor and Neuronal Calcium Sensor-1 analyzed by fluorescence anisotropy Biochemistry 50(41):8780-91 PMID:21875085 PMCID: (no number)
Tacelosky DM, Creecy AE, Shanmugavelandy SS, Smith JP, Claxton DF, Adair JH, Kester M, Barth BM (2012) Calcium phosphosilicate nanoparticles for imaging and photodynamic therapy of cancer Discov Med 13(71):275-85 PMCID: (no number)
Barth BM, Shanmugavelandy SS, Tacelosky DM, Kester M, Morad SA, Cabot MC (2013) Gaucher's disease and cancer: a sphingolipid perspective Crit Rev Oncog.18(3):221-34 PMCID: PMC3604879