PRINCIPAL INVESTIGATORS

Toni S. Shippenberg, Ph.D., Senior Investigator

Chief, Integrative Neuroscience Branch
Chief, Integrative Neuroscience Section

Post-doctoral training - Neuropharmacology Department, Max-Planck Institute for Psychiatry (advisor Professor Albert Herz)

Ph. D. - Pharmacology, Baylor College of Medicine

B.A. - Neuroscience, Colgate University

RESEARCH INTERESTS

Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use continues, motivation for natural rewards that normally drive behavior decreases and behavior that was goal-oriented becomes habitual in nature. The Integrative Neuroscience Section seeks to identify the contribution of endogenous opioid peptide systems to the functional restructuring of brain circuits that occurs during drug use and that leads to the hedonic dysregulation that characterizes addiction. A second focus of the Section is the identification of effective, non-opioid targets for the treatment of persistent pain. On-going studies are examining: (i) the cellular and neurochemical mechanisms by which opioid systems modulate neurotransmission within the prefrontal-cortico-striatal loop, a brain circuit that regulates mood, motivation, and the behavioral effects of various drugs of abuse; (ii) whether dysregulation of these systems is associated with enhanced vulnerability to drug and alcohol addiction and (iii) whether targeting a novel class of proteins that regulates excitatory amino acid transmission can prevent persistent pain arising from diverse etiologies. Towards that end, the Section employs animal models in conjunction with in-vivo analytical techniques to quantify neurotransmitter and neuropeptide dynamics in the behaving animal and live cell immnofluorescence confocal microscopy to monitor protein function and protein-protein interactions in real time. The long-term goal of our studies is the development of effective therapeutics for the treatment of pain and addiction.

Selected Publications:

1. Zapata, A., Minney, V.L., Shippenberg, T.S. (2010).  Shift from goal-directed to habitual cocaine seeking after prolonged experience in rats. J Neurosci, 30(46):15457-63.

2. Oz, M., Libby, T., Kivell, B., Jaligam, V., Ramamoorthy, S., Shippenberg, T.S. (2010).  Real-time, spatially resolved analysis of serotonin transporter activity and regulation using the fluorescent substrate, ASP+.  J Neurochem, 114(4):1019-29.

3. Chefer, V.I., Denoroy, L., Zapata, A., Shippenberg, T.S. (2009).  Mu opioid receptor modulation of somatodendritic dopamine overflow: GABAergic and glutamatergic mechanisms.  Eur J Neurosci, 30(2):272-8.

4. Shippenberg , T.S., Chefer, V.I., Thompson, A.C.  (2009). Delta-opioid receptor antagonists prevent sensitization to the conditioned rewarding effects of morphine.  Biol Psychiatry, 65(2), 169-74.

5. Schepers, R.J., Mahoney, J.L., Shippenberg, T.S.  (2008). Inflammation-induced changes in rostral ventromedial medulla mu and kappa opioid receptor mediated antinociception.  Pain, 136(3), 320-30.

6. Scheper, R.J., Mahoney,  J.L., Gehrke, B. & Shippenberg, T.S.  (2008). Endogenous k-opioid receptor systems inhibit mechanical nociception during inflammatory pain.  Pain,  138(2), 423-39.

7. Zapata, A., Kivell, B., Han, Y., Javitch, J.A., Bolan, E.A., Kuraguntla, D., Jaligam, V., Oz, M., Jayanthi, L.D., Samuvel, D.J., Ramamoorthy, S., Shippenberg, T.S.  (2007). Regulation of dopamine transporter function and cell surface expression by D3 dopamine receptors.  J Biol Chem, 282(49), 35842-54.

8. Bolan,  E.A., Kivell, B., Jaligam, V., Oz,  M., Jayanthi,  L.D., Han, Y., Sen, N., Urizar, E., Gomes, I., Devi,  L.A., Ramamoorthy,  S.,  Javitch,  J.A. , Zapata,  A., Shippenberg,  T.S.  (2007).  D2 receptors regulate dopamine transporter function via an extracellular signal-regulated kinases 1 and 2-dependent and phosphoinositide 3 kinase-independent mechanism.  Mol Pharmacol, 71(5):1222-32.

9. Margolis, E.B., Lock, H., Chefer, V.I., Shippenberg, T.S., Hjelmstad, G.O., Fields, H.L. (2006). Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex.  Proc Natl Acad Sci U S A, 103(8), 2938-42.

10. Chefer V.I., Czyzyk, T., Bolan, E.A., Moron,  J., Pintar, J.E., Shippenberg, T.S. (2005). Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine.   J Neurosci, 25(20), 5029-37.