This proposal is a career development plan for Dr. Michael R. Bruchas, a post-doctoral fellow trained as a pharmacologist, who is interested in a research career studying the molecular, cellular, and behavioral components of stress and addiction. The applicant will be mentored by Dr. Chavkin in several neuroscience approaches including animal models of stress and addiction. The proposed project is to be conducted at University of Washington, in the Department of Pharmacology, a strong and enriching environment for neuroscience research. The research training proposal concerns Kappa opioid receptor (KOR) signaling and noradrenergic mechanisms in stress and drug seeking. Recently, Kappa receptors were shown to regulate stress-induced behavioral responses to drugs of abuse, including stress-induced reinstatement, and potentiation of cocaine-conditioned place preference. We and others have also demonstrated that kappa opioid receptors couple to mitogen-activated protein kinase (MARK) signaling cascades, and that this activation is required for KOR-mediated behavioral responses. In addition, it has been suggested that KOR systems interact with noradrenergic systems, although the behavioral consequences, molecular and cellular nature of these interactions are poorly understood. During the """"""""mentored phase"""""""" (Aim 1) we will investigate KOR-mediated p38 MARK signaling as it relates to neuroanatomical and behavioral contexts using conditional and viral knockdown strategies, immunohistochemical and biochemistry.
In aim 2, we will investigate noradrenergic systems, the mediation of KOR-dependent behavioral responses, and interaction between both systems. During the independent phase (Aim 3 and 4) Dr. Bruchas will investigate the anatomical relationships (receptors, cell types, regions) where opioid and noradrenergic circuits converge, and their respective roles in drug-seeking behavior. This project aims to define the pharmacological and physiological mechanisms of stress-induced drug seeking by identifying new receptor systems and signaling pathways, and sets the stage for Dr. Bruchas'independence as a principal investigator.

Public Health Relevance

This proposal will examine the neuronal mechanisms involved in drug seeking behavior. By understanding these neuronal processes we will gain a better understanding of how stress modulates addictive behavior.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Career Transition Award (K99)
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Human Development Research Subcommittee (NIDA)
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Wu, Da-Yu
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University of Washington
Schools of Medicine
United States
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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
Al-Hasani, Ream; Bruchas, Michael R (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363-81
Bruchas, Michael R; Schindler, Abigail G; Shankar, Haripriya et al. (2011) Selective p38ýý MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 71:498-511
Melief, Erica J; Miyatake, Mayumi; Bruchas, Michael R et al. (2010) Ligand-directed c-Jun N-terminal kinase activation disrupts opioid receptor signaling. Proc Natl Acad Sci U S A 107:11608-13
Bruchas, Michael R; Chavkin, Charles (2010) Kinase cascades and ligand-directed signaling at the kappa opioid receptor. Psychopharmacology (Berl) 210:137-47
Lyssand, John S; Whiting, Jennifer L; Lee, Kyung-Soon et al. (2010) Alpha-dystrobrevin-1 recruits alpha-catulin to the alpha1D-adrenergic receptor/dystrophin-associated protein complex signalosome. Proc Natl Acad Sci U S A 107:21854-9
Bruchas, M R; Land, B B; Chavkin, C (2010) The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res 1314:44-55
Bruchas, Michael R; Land, Benjamin B; Lemos, Julia C et al. (2009) CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS One 4:e8528
Land, Benjamin B; Bruchas, Michael R; Schattauer, Selena et al. (2009) Activation of the kappa opioid receptor in the dorsal raphe nucleus mediates the aversive effects of stress and reinstates drug seeking. Proc Natl Acad Sci U S A 106:19168-73