This proposal is an extention of a career development award (5K99-DA025182-02) for Dr. Michael R. Bruchas, who is trained as a pharmacologist, and has focused his research career studying the molecular, cellular, and behavioral components of stress and addiction. The proposed project, is to be conducted at Washington University-St. Louis, in the Departments of Anesthesiology &Anatomy/Neurobiology, a strong and enriching environment for neuroscience research. The proposal's overall goal is to better understand the neuronal relationship between stress and drug seeking. Specifically, it concerns Kappa opioid receptor (KOR) signaling and noradrenergic mechanims in stress and drug seeking. Recently, Kappa opioid receptors were shown to regulate stress-induced behavioral responses to drugs of abuse, including stress-induced reinstatement (termed relapse in humans), and potentiation of cocaine-conditioned place preference. We and others have also demonstrated that kappa opioid receptors couple to mitogen-activated protein kinase (MAPK) signaling cascade, that is required for these behaviors. 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. This proposal has 2 specific aims: 1) To determine the anatomical brain regions, subpopulations, and cell types where kappa opioid and noradrenergic circuits converge following behavioral (stress) and pharmacological stimuli. 2) To determine how stress and dynorphin/KOR activation regulate noradrenergic circuits to ultimately influence cocaine and methamphetamine reward. We will investigate noradrenergic systems, the mediation of KOR-dependent behavioral responses, and interaction between both systems. This project 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's goal is to further define the pharmacological and physiological mechanisms of stress-induced drug reward by dissecting the dynorphinergic and noradrenergic brain circuitry involved in the interactions between stress and drugs of abuse.

Public Health Relevance

This proposol will examine the neuronal mechanisms involved in stress-induced drug seeking behavior, understanding these neuronal processes we will gain a better understanding of how stress modulates addictive behavior, and potentially identify novel therapeutic receptor targets for addiction treatment.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Transition Award (R00)
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Study Section
Special Emphasis Panel (NSS)
Program Officer
Wu, Da-Yu
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Washington University
Schools of Medicine
Saint Louis
United States
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Siuda, Edward R; Al-Hasani, Ream; McCall, Jordan G et al. (2016) Chemogenetic and Optogenetic Activation of G?s Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States. Neuropsychopharmacology 41:2011-23
Siuda, Edward R; McCall, Jordan G; Al-Hasani, Ream et al. (2015) Optodynamic simulation of ?-adrenergic receptor signalling. Nat Commun 6:8480
Chang, Steven D; Bruchas, Michael R (2014) Functional selectivity at GPCRs: new opportunities in psychiatric drug discovery. Neuropsychopharmacology 39:248-9
Portugal, George S; Al-Hasani, Ream; Fakira, Amanda K et al. (2014) Hippocampal long-term potentiation is disrupted during expression and extinction but is restored after reinstatement of morphine place preference. J Neurosci 34:527-38
Al-Hasani, Ream; McCall, Jordan G; Foshage, Audra M et al. (2013) Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism. Neuropsychopharmacology 38:2484-97
McCall, Jordan G; Kim, Tae-Il; Shin, Gunchul et al. (2013) Fabrication and application of flexible, multimodal light-emitting devices for wireless optogenetics. Nat Protoc 8:2413-2428
Al-Hasani, Ream; McCall, Jordan G; Bruchas, Michael R (2013) Exposure to chronic mild stress prevents kappa opioid-mediated reinstatement of cocaine and nicotine place preference. Front Pharmacol 4:96
Kim, Tae-il; McCall, Jordan G; Jung, Yei Hwan et al. (2013) Injectable, cellular-scale optoelectronics with applications for wireless optogenetics. Science 340:211-6
Zhang, Nancy R; Planer, William; Siuda, Edward R et al. (2012) Serine 363 is required for nociceptin/orphanin FQ opioid receptor (NOPR) desensitization, internalization, and arrestin signaling. J Biol Chem 287:42019-30
Crock, Lara W; Kolber, Benedict J; Morgan, Clinton D et al. (2012) Central amygdala metabotropic glutamate receptor 5 in the modulation of visceral pain. J Neurosci 32:14217-26

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