Principal Investigator: Michael R Bruchas
Abstract: DESCRIPTION (provided by applicant): Activation of kappa opioid receptors (KOR) in humans elicits dysphoria, and KOR activation by agonists or by stress-induced dynorphin release in rodents produces reinstatement of drug seeking. The dysphoric/aversive effects of dynorphin/KOR system activity have been linked to increased cocaine self-administration, and cause reinstatement of cocaine seeking behaviors. While many reports of KOR dependent regulation of cocaine, morphine, and alcohol seeking exist, there are very few studies examining the role and mechanisms of stress-induced dynorphin-KOR activity on nicotine reinstatement. Despite recent efforts, nicotine use is at an all time high, is responsible for millions of deaths each year and remains one of the most difficult drugs to quit. The neural networks and cellular-molecular mechanisms responsible for KOR-dependent nicotine reinstatement are not understood. Given nicotine's diverse pharmacological profile and interaction within multiple circuits, understanding how dynorphin neural circuits and KOR activation causes nicotine reinstatement will provide novel, valuable, and important insights and suggest new therapeutic approaches to the treatment and prevention of stress-related nicotine relapse. While evidence shows a key role for KOR-dependent inhibition in ventral tegmental (VTA) nucleus Accumbens (NAc) circuits, recent evidence has strongly implicated dynorphin activation of p38 MAPK in the serotonergic dorsal raphe nucleus (DRN) as required for KOR-dependent reinstatement and aversion. The role of each pathway in nicotine reinstatement is not known, so we propose to methodically dissect how activation of KOR, either by stress-induced dynorphin, optogenetic modulation of dynorphin/CRF release, or systemic administration of a selective KOR agonist, results in reinstatement of nicotine conditioned place preference. To accomplish this we propose the following Aims using an array of multidisciplinary approaches: 1) to determine the role of dynorphin/KOR activity in serotonergic circuits as necessary and sufficient for stress-induced nicotine preference using viral rescue ("gain of function"), in vivo pharmacology, and mouse genetics to assess KOR in circuits mediating stress-induced and dynorphin/KOR-mediated reinstatement of nicotine preference. 2) to measure the effects of p38 MAPK activation in circuits required for stress-induced reinstatement of nicotine preference. 3) To use a novel mouse line coupled with optogenetic approaches to dissect dynorphinergic neural inputs into key sites of KOR action mediating reinstatement of nicotine preference. The proposed studies would test our central hypothesis that stress and KOR-induced reinstatement of nicotine reward is mediated as consequence of dynorphin-KOR-dependent activation of downstream signaling pathways in selected neural circuits.
Funding Period: 2013-08-15 - 2018-04-30
more information: NIH RePORT

Top Publications

  1. pmc Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism
    Ream Al-Hasani
    1 Basic Research Division, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA 2 Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, USA
    Neuropsychopharmacology 38:2484-97. 2013

Detail Information


  1. pmc Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism
    Ream Al-Hasani
    1 Basic Research Division, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA 2 Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO, USA
    Neuropsychopharmacology 38:2484-97. 2013
    ..These results identify a previously unknown interaction between KORs and NA systems and suggest a NA regulation of KOR-dependent reinstatement of cocaine CPP...

Research Grants30

    Fulton T Crews; Fiscal Year: 2013
    ..The ARC will conduct, promote, support, and mentor research on alcoholic pathology and educate broad groups of health professionals and youth in North Carolina. ..
  2. Development of GABABeta Receptor Compounds for Nicotine Dependence
    Athina Markou; Fiscal Year: 2013
    ..This multidisciplinary research program integrates the complementary expertise of the participating scientists to provide innovative potential therapeutics for nicotine dependence in humans. ..
  3. Host and Parasite Determinants in Human Leishmaniasis
    Edgar M Carvalho; Fiscal Year: 2013
    ..abstract_text> ..
  4. Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA)
    Christopher J Evans; Fiscal Year: 2013
    ..Balleine, Bonci, Koob, Levitt, Nestler and Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a Pilot Program for the center. ..
  5. Pilot Longitudinal Data Collection to Inform Public Health_Fragile X Syndrome
    W Ted Brown; Fiscal Year: 2013
  6. Substance Abuse Research - Medications Development Center
    JOY MARIE SCHMITZ; Fiscal Year: 2013
    ..abstract_text> ..
  7. Translational Methamphetamine AIDS Research Center (TMARC)
    Igor Grant; Fiscal Year: 2013
    ..TMARC's ultimate vision is to become a national resource for translational multidisciplinary research and training in the neuropathogenesis of HIV and substance use. ..
  8. Endogenous Cannabinoids and Brain Function
    Aron H Lichtman; Fiscal Year: 2013
    ..Ultimately, the knowledge gained from this basic research will yield novel therapeutic targets that can be exploited with the pharmacological agents developed here. PROGRAM CHARACTERISTICS ..
  9. p38 MAPK Mechanisms of Kappa Opioid-Induced Aversion
    Charles Chavkin; Fiscal Year: 2013
  10. Opioid and Noradrenergic Mechanisms in Stress and Drug Seeking
    Michael R Bruchas; Fiscal Year: 2013
    ..abstract_text> ..
  11. Iowa Cochlear Implant Clinical Research Center Project VI
    Bruce Jay Gantz; Fiscal Year: 2013
    ..The five research projects are highly integrated and depend on data from each other to answer the experimental questions. ..
  12. Development of Novel Opioid Peptides for Cocaine Abuse
    Jane V Aldrich; Fiscal Year: 2013
    ..This research is expected to produce candidates that can be rationally and productively advanced into late preclinical development as potential treatments for cocaine addiction and relapse. ..
  13. Novel Ligands that Selectively Desensitize alpha4beta nAChRs for Smoking Cessatio
    Kenneth J Kellar; Fiscal Year: 2013
    ..A major goal of our proposed research is that it will lead to the development a new class of CNS therapeutics, selective a4p2 nAChR desensitizers, to aid smoking cessation. ..
  14. Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology
    Laura M Bohn; Fiscal Year: 2013
    ..We are supported by a GPCR pharmacologist with extensive experience in industry-level assay development for high throughput drug discovery as well as an expert in pharmacokinetic evaluations. ..
  15. Prefrontal control of kappa-opioid receptor mediated stress-induced relapse.
    Peter A Groblewski; Fiscal Year: 2013
    ..Overall, these experiments are intended to further our understanding of how the KOR system is involved in the convergence of the stress and reward pathways that is required for expression of stress- induced relapse. ..
  16. Oral Mucosal Immunity in Vulnerable HIV Infected Populations
    Aaron Weinberg; Fiscal Year: 2013
    ..All the data will be subjected to rigorous scientific scrutiny through meetings between the PIs and an External Advisory Panel that will be organized through the Administrative Core (Core A). ..
    HERBERT DAVID KLEBER; Fiscal Year: 2013
    ..abstract_text> ..
  18. Cocaine-induced Changes of Mesocorticolimbic Circuitry and Drug-seeking Behavior
    Deanne M Buffalari; Fiscal Year: 2013
    ..Issues examined in this proposal and in future studies will advance our understanding of the role of stress in addiction, as well as facilitate approaches for the successful treatment o addiction. ..
  19. Development of Orexin-1 Receptor Antagonists for Drug Addiction
    Paul J Kenny; Fiscal Year: 2013
    ..This integrated multidisciplinary research plan will capitalize on the unique drug discovery capabilities at Scripps Florida, and promises to yield novel therapeutic entities for the prevention of relapse in human tobacco smokers. ..