The rationale of this study is to understand the mechanims underlying kappa opioid receptor (KOR) mediated stress-induced potentiation of cocaine conditioned place preference (CPP) from a signal transduction and anatomical perspective. This research proposal will examine the molecular and physiological mechanisms underlying the KOR-mediated stress response. Preliminary results suggest that this response is mediated by KOR-induced MAPK activation. Using striatal brain region homogenates, we will examine how stress (modified forced swim) changes reward circuitry in a KOR-dependent fashion. This proposed study will assess the role of G-protein coupled receptor kinase (GRK3) shown in preliminary studies to be necessary for the KOR-mediated stress response. In addition, these studies will examine the cell types and neuronal populations that these stress-induced KOR-mediated events occur by using antibodies specific for the the phosphorylated KOR (activated), MAPKs and neuronal markers. In doing so we will use tissue immunohistochemistry and primary culture techniques to understand the spatial and temporal relationship of KOR-mediated signal transduction following stress.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DA020430-02
Application #
7123468
Study Section
Special Emphasis Panel (ZDA1-MXS-M (07))
Program Officer
Babecki, Beth
Project Start
2005-09-01
Project End
2008-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$48,796
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Bruchas, Michael R; Xu, Mei; Chavkin, Charles (2008) Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2. Neuroreport 19:1417-22
Land, Benjamin B; Bruchas, Michael R; Lemos, Julia C et al. (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. J Neurosci 28:407-14
Petraschka, M; Li, S; Gilbert, T L et al. (2007) The absence of endogenous beta-endorphin selectively blocks phosphorylation and desensitization of mu opioid receptors following partial sciatic nerve ligation. Neuroscience 146:1795-807
Bruchas, Michael R; Yang, Tao; Schreiber, Selena et al. (2007) Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase. J Biol Chem 282:29803-11
Xu, Mei; Bruchas, Michael R; Ippolito, Danielle L et al. (2007) Sciatic nerve ligation-induced proliferation of spinal cord astrocytes is mediated by kappa opioid activation of p38 mitogen-activated protein kinase. J Neurosci 27:2570-81
Bruchas, Michael R; Land, Benjamin B; Aita, Megumi et al. (2007) Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. J Neurosci 27:11614-23