The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence

Summary

Principal Investigator: Brendan M Walker
Abstract: DESCRIPTION (provided by applicant): A fundamental characteristic of excessive alcohol use is the comorbidity of alcohol dependence and disorders of affect. Self-medication of these negative affective states likely contributes to excessive alcohol use and relapse. Negative affective states produced by chronic alcohol exposure result from neuroadaptations in motivational and affective neurocircuitry that are not yet understood. The principal investigator's long-term goal is to identify effective pharmacotherapeutic targets for the treatment of alcoholism. The objective of this application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in dynorphin / kappa-opioid systems that occur in response to chronic alcohol exposure and contribute to attenuated motivational and affective states. The central hypothesis is that compensatory neuroadaptations in dynorphin / kappa-opioid systems oppose the acute effects of alcohol, and promote excessive alcohol intake by altering negative affective behaviors. The rationale for the proposed studies is that identification of dynorphin targets will enable the development of pharmacotherapies designed to alleviate motivational and affective symptoms produced by alcohol dependence. The hypothesis will be tested by pursuing the following specific aims: Aim #1 will evaluate kappa opioid receptor antagonism within specific sites of the extended amygdala during acute withdrawal. Aim #2 will site-specifically evaluate the role of extended amygdala dynorphin systems in depressive- and anxiety-like behavior. Specific Aim #3 will maximize dependence-induced alterations in negative affective behaviors during acute and protracted withdrawal. All three aims will utilize animal models of ethanol reinforcement and affective behavior to allow for the systematic investigation of neurotransmitter systems and neurocircuitry that contribute to altered motivational and affective states produced by chronic ethanol exposure. These three specific aims will collectively help to identify important neuroadaptations that result from chronic alcohol exposure and provide much needed information regarding the neurocircuitry involved in altered motivational and affective systems. Such a contribution is significant because it will help to develop pharmacotherapeutic targets for the treatment of alcoholism that focus on the removal of attenuated motivational and negative affective states;a strategy that should greatly increase medication compliance and decrease rates of relapse. PUBLIC HEALTH RELEVANCE: This proposal is relevant to public health and will have an important positive impact because there are currently no pharmacotherapies designed to alleviate the negative affective and attenuated motivational aspects of alcohol withdrawal and dependence. In addition to the site-specific investigation of dynorphin / kappa-opioid systems in reinforcement paradigms, the benefits of this proposal are the assessment of dynorphin / kappa-opioid systems in depressive- and anxiety-like behaviors associated with alcohol dependence. The proposed experiments will assist with the development of pharmacological targets for alcoholism based on the alleviation of negative affect and result in increased compliance and treatment success for the individual and less alcoholism-associated societal costs.
Funding Period: 2011-04-01 - 2017-07-31
more information: NIH RePORT

Top Publications

  1. pmc κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats
    Kathryn A Nealey
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Mail Code 644820, Pullman, WA 99164 4820, USA
    Neuropharmacology 61:35-42. 2011
  2. pmc The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors
    Jessica L Kissler
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington
    Biol Psychiatry 75:774-82. 2014
  3. pmc Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptors
    Anthony L Berger
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Pullman, WA, USA
    Neuropsychopharmacology 38:647-54. 2013
  4. pmc Alcohol-induced plasticity in the dynorphin/kappa-opioid receptor system
    Sunil Sirohi
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University Pullman, WA, USA
    Front Mol Neurosci 5:95. 2012
  5. pmc The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats
    Angela M Williams
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, 100 Dairy Road, 644820, Pullman, WA 99164 4820, USA
    Psychopharmacology (Berl) 223:75-88. 2012
  6. pmc Conceptualizing withdrawal-induced escalation of alcohol self-administration as a learned, plasticity-dependent process
    Brendan M Walker
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology and Graduate Program in Neuroscience, Alcohol and Drug Abuse Research Program, Translational Addictions Research Center, Washington State University, Pullman, WA 99164, USA
    Alcohol 46:339-48. 2012
  7. pmc Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence
    Brendan M Walker
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology and Graduate Program in Neuroscience, Alcohol and Drug Abuse Research Program, Translational Addiction Research Center, Washington State University, Pullman, WA 99164, USA
    Alcohol 46:359-70. 2012
  8. pmc Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems
    Alexander W Smith
    Department of Psychology, Washington State University, Pullman, WA 99164 4820, USA
    Neurobiol Learn Mem 96:199-206. 2011
  9. pmc Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats
    Brendan M Walker
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Graduate Program in Neuroscience, Washington State University, Pullman, WA, USA
    Neuropsychopharmacology 38:2278-85. 2013

Research Grants

  1. Southern California Research Center for ALPD and Cirrhosis
    Hidekazu Tsukamoto; Fiscal Year: 2013
  2. Ethanol and Peptidergic Systems in the Central Amygdala
    Scott D Moore; Fiscal Year: 2013
  3. Regulation of Ethanol Effects on Synaptic Transmission
    Marisa Roberto; Fiscal Year: 2013
  4. ENVIRONMENTAL APPROACHES TO PREVENTION
    Paul J Gruenewald; Fiscal Year: 2013
  5. MOLECULAR AND CELLULAR PATHOGENESIS IN ALCOHOLISM
    Fulton T Crews; Fiscal Year: 2013
  6. Adolescent Alcohol,Dysregulated Stress System, and PTSD Vulnerability
    GERHARD H SCHULTEIS; Fiscal Year: 2013
  7. Emory Alcohol and Lung Biology Center
    DAVID MARSHALL GUIDOT; Fiscal Year: 2013
  8. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
  9. Ethanol and stress effects on monoamine neurotransmission
    Sara R Jones; Fiscal Year: 2013

Detail Information

Publications10

  1. pmc κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent rats
    Kathryn A Nealey
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Mail Code 644820, Pullman, WA 99164 4820, USA
    Neuropharmacology 61:35-42. 2011
    ....
  2. pmc The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors
    Jessica L Kissler
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington
    Biol Psychiatry 75:774-82. 2014
    ....
  3. pmc Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptors
    Anthony L Berger
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Pullman, WA, USA
    Neuropsychopharmacology 38:647-54. 2013
    ..Taken together, this study implicates negative affective states induced by both alcohol withdrawal and conditioned stimuli as being produced, in part, by activity of the DYN/KOR system...
  4. pmc Alcohol-induced plasticity in the dynorphin/kappa-opioid receptor system
    Sunil Sirohi
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University Pullman, WA, USA
    Front Mol Neurosci 5:95. 2012
    ..The present review will discuss alcohol-induced plasticity in the DYN/KOR system and how these neuroadaptations could contribute to excessive alcohol seeking and consumption...
  5. pmc The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar rats
    Angela M Williams
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, 100 Dairy Road, 644820, Pullman, WA 99164 4820, USA
    Psychopharmacology (Berl) 223:75-88. 2012
    ..Once dependent on alcohol or opioids, negative affect may accompany withdrawal. Dependent individuals are hypothesized to "self-medicate" in order to cope with withdrawal, which promotes escalated alcohol and drug use...
  6. pmc Conceptualizing withdrawal-induced escalation of alcohol self-administration as a learned, plasticity-dependent process
    Brendan M Walker
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology and Graduate Program in Neuroscience, Alcohol and Drug Abuse Research Program, Translational Addictions Research Center, Washington State University, Pullman, WA 99164, USA
    Alcohol 46:339-48. 2012
    ....
  7. pmc Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence
    Brendan M Walker
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology and Graduate Program in Neuroscience, Alcohol and Drug Abuse Research Program, Translational Addiction Research Center, Washington State University, Pullman, WA 99164, USA
    Alcohol 46:359-70. 2012
    ....
  8. pmc Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems
    Alexander W Smith
    Department of Psychology, Washington State University, Pullman, WA 99164 4820, USA
    Neurobiol Learn Mem 96:199-206. 2011
    ..Thus, the present data identified that an intact MMP system is required for the escalated responding that occurs during acute withdrawal in dependent animals and implicate such escalation as a learned response...
  9. pmc Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats
    Brendan M Walker
    Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Graduate Program in Neuroscience, Washington State University, Pullman, WA, USA
    Neuropsychopharmacology 38:2278-85. 2013
    ..Furthermore, KOR-mediated impulsivity has implications for numerous neuropsychiatric disorders. ..

Research Grants30

  1. Southern California Research Center for ALPD and Cirrhosis
    Hidekazu Tsukamoto; Fiscal Year: 2013
    ..abstract_text> ..
  2. Ethanol and Peptidergic Systems in the Central Amygdala
    Scott D Moore; Fiscal Year: 2013
    ....
  3. Regulation of Ethanol Effects on Synaptic Transmission
    Marisa Roberto; Fiscal Year: 2013
    ..abstract_text> ..
  4. ENVIRONMENTAL APPROACHES TO PREVENTION
    Paul J Gruenewald; Fiscal Year: 2013
    ....
  5. MOLECULAR AND CELLULAR PATHOGENESIS IN ALCOHOLISM
    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. ..
  6. Adolescent Alcohol,Dysregulated Stress System, and PTSD Vulnerability
    GERHARD H SCHULTEIS; Fiscal Year: 2013
    ....
  7. Emory Alcohol and Lung Biology Center
    DAVID MARSHALL GUIDOT; Fiscal Year: 2013
    ..abstract_text> ..
  8. BEHAVIORAL GENOMICS OF ALCOHOL NEUROADAPTATION
    John C Crabbe; Fiscal Year: 2013
    ..An Education and Outreach component trains pre- and post-doctoral students in alcohol research, disseminates research findings to the public, and engages in a range of activities with elementary-to-high school students. ..
  9. Ethanol and stress effects on monoamine neurotransmission
    Sara R Jones; Fiscal Year: 2013
    ..These aims will provide a comprehensive assessment of monoamine changes induced by chronic ethanol exposure and the differential impact of a stress challenge on a background of chronic ethanol adaptations. ..