Drug addiction is a progressive disorder characterized by compulsive drug-taking behavior and high rates of relapse, even after prolonged periods of abstinence. The costs associated with drug addiction, factoring in lost productivity, health problems, and crime, are estimated at $600 billion per year in the United States alone. Our limited understanding of the neurochemical, molecular, and cellular mechanisms underlying drug reward, craving, and relapse has impeded our ability to confront this major public health issue effectively. The premise of this proposal is that a better understanding of the signaling pathways that mediate the cellular and behavioral effects of drugs of abuse will improve our ability to combat addiction. The focus of this proposal is on a form of inhibitory signaling and its relevance to the cellular and behavioral effects of acute and repeated cocaine exposure. Our work over the last decade has revealed that the behavioral effects of many drugs of abuse, including cocaine, are dependent on G protein-gated inwardly-rectifying K+ (Girk/KIR3) channels. More recently, we have found that in vivo cocaine exposure suppresses Girk signaling in dopamine (DA) neurons of the ventral tegmental area (VTA) and glutamatergic output neurons of the medial prefrontal cortex (Layer 5/6 mPFC pyramidal neurons), neuron populations instrumental to the reward-related behavioral effects of acute and repeated cocaine exposure. The goals of this project are to understand how cocaine suppresses Girk signaling in VTA DA and Layer 5/6 mPFC pyramidal neurons, and how these adaptations influence reward- related behavior and excitatory neurotransmission in the mesocorticolimbic reward circuitry. The novel conceptual framework is that Girk signaling in VTA DA and Layer 5/6 mPFC pyramidal neurons is an early "addiction barrier" that is overcome by cocaine exposure, paving the way for enduring adaptations linked to craving and relapse. Proposed studies will combine slice electrophysiological and behavioral assessments, with both approaches utilizing a novel array of mutant mouse lines and exploiting recent progress in our ability to perturb Girk signaling with unprecedented molecular, anatomic, and temporal precision. Efforts will center on three specific aims: 1) To understand the acute cocaine-induced suppression of Girk signaling in VTA DA neurons, 2) To understand the repeated cocaine-induced suppression of Girk signaling in mPFC pyramidal neurons, and 3) To probe the relevance of Girk signaling in the VTA and mPFC to reward-related behavior. Successful completion of this project will yield novel insights into the relevance of Girk signaling to reward related behavior, while also highlighting the role of such signaling in the cocaine-induced neuroadaptations that underlie key facets of addiction, including craving and relapse. Accordingly, this project targets multiple strategic goals of the National Institute on Drug Abuse, including prevention and treatment objectives that hinge on expanding our understanding of basic neurobiology as it relates to circuitry underlying addiction.

Public Health Relevance

Drug addiction is a chronic progressive disease characterized by compulsive drug-taking and high rates of relapse, even after prolonged periods of abstinence. Our limited understanding of the genes, signaling pathways, and brain regions mediating the effects of abused drugs has hindered the development of approaches designed to prevent or treat addiction. The proposed research will test a novel hypothesis concerning the contribution of a specific form of inhibitory signaling to the cellular and behavioral effects of cocaine exposure, paving the way toward a more comprehensive understanding of addiction.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DA034696-02
Application #
8701263
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Sorensen, Roger
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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Wydeven, Nicole; Marron Fernandez de Velasco, Ezequiel; Du, Yu et al. (2014) Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297. Proc Natl Acad Sci U S A 111:10755-60
Lujan, Rafael; Marron Fernandez de Velasco, Ezequiel; Aguado, Carolina et al. (2014) New insights into the therapeutic potential of Girk channels. Trends Neurosci 37:20-9
Hearing, Matthew; Kotecki, Lydia; Marron Fernandez de Velasco, Ezequiel et al. (2013) Repeated cocaine weakens GABA(B)-Girk signaling in layer 5/6 pyramidal neurons in the prelimbic cortex. Neuron 80:159-70