This is an application for a Senior Scientist K05 award for the research career development of Dr. Charles Chavkin who is the Allan and Phyllis Treuer Chair of Pain Research in the Department of Pharmacology at the University of Washington. Dr. Chavkin received his PhD training in pharmacology at Stanford University, completed postdoctoral training at the Salk Institute and Scripps Clinic before joining the faculty at the University of Washington. He is currently the principal investigator of RO1-DA11672-06, R01-DA16898-02, P01-DA15916-03, and director of T32-DA07278-11.
The research aims of these grants are respectively designed to 1) study the phosphorylation mechanisms regulating of opioid receptor activation of Kir3 type potassium channels, 2) study the cellular mechanisms responsible for behavioral stress-induced potentiation of the cocaine reward, 3) study the mechanisms of opioid analgesic tolerance using transgenic mouse models, and 4) supervise training of predoctoral and postdoctoral fellows in molecular approaches of drug abuse research. The purpose of this K05 application is to consolidate salary support for Dr. Chavkin and to reduce his non-research related administrative responsibilities. This plan has the full support of the department of pharmacology Chair and the Vice-Dean for Research in the School of Medicine. The long term goals of the proposed research plan are to further develop a multidisciplinary approach to the study of the actions of endogenous dynorphin opioid neuropeptides in drug addiction. The dynorphin/kappa opioid system seems to function as key mediators of the response to chronic stress in ways that potentiate the rewarding properties of cocaine. Understanding how chronic stress increases the risk of drug addiction and increases the risk of relapse has important therapeutic implications. The multidisciplinary approach necessary to address these questions requires molecular biological tools to define the targets of drug action, molecular pharmacological methods to resolve the cellular events underlying the responses, electrophysiological methods to define the actions of drugs on the neurons affected, anatomical methods to define the neural circuits and sites of drug action, and behavioral methods to provide relevant and valid stimuli to the nervous system. The award would greatly strengthen the candidate's ability to provide leadership in this integrative effort.
|Ehrich, Jonathan M; Messinger, Daniel I; Knakal, Cerise R et al. (2015) Kappa Opioid Receptor-Induced Aversion Requires p38 MAPK Activation in VTA Dopamine Neurons. J Neurosci 35:12917-31|
|Kuhar, Jamie Rose; Bedini, Andrea; Melief, Erica J et al. (2015) Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms. Cell Signal 27:1799-806|
|Groblewski, Peter A; Zietz, Chad; Willuhn, Ingo et al. (2015) Repeated stress exposure causes strain-dependent shifts in the behavioral economics of cocaine in rats. Addict Biol 20:297-301|
|Chavkin, Charles; Schattauer, Selena S; Levin, Jamie R (2014) Arrestin-mediated activation of p38 MAPK: molecular mechanisms and behavioral consequences. Handb Exp Pharmacol 219:281-92|
|Smith, Jeffrey S; Angel, Thomas E; Chavkin, Charles et al. (2014) Characterization of individual mouse cerebrospinal fluid proteomes. Proteomics 14:1102-6|
|Ehrich, Jonathan M; Phillips, Paul E M; Chavkin, Charles (2014) Kappa opioid receptor activation potentiates the cocaine-induced increase in evoked dopamine release recorded in vivo in the mouse nucleus accumbens. Neuropsychopharmacology 39:3036-48|
|Chavkin, Charles; Ehrich, Jonathan M (2014) How does stress-induced activation of the kappa opioid system increase addiction risk? Biol Psychiatry 76:760-2|
|Soden, Marta E; Jones, Graham L; Sanford, Christina A et al. (2013) Disruption of dopamine neuron activity pattern regulation through selective expression of a human KCNN3 mutation. Neuron 80:997-1009|
|Chavkin, Charles (2013) Dynorphin--still an extraordinarily potent opioid peptide. Mol Pharmacol 83:729-36|
|Williams, John T; Ingram, Susan L; Henderson, Graeme et al. (2013) Regulation of ?-opioid receptors: desensitization, phosphorylation, internalization, and tolerance. Pharmacol Rev 65:223-54|
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