Genomes and Genes
The Role of Dynorphin / Kappa-Opioid Systems in Alcohol Dependence
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
- κ-opioid receptors are implicated in the increased potency of intra-accumbens nalmefene in ethanol-dependent ratsKathryn 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....
- The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptorsJessica L Kissler
Laboratory of Alcoholism and Addictions Neuroscience, Department of Psychology, Washington State University, Pullman, Washington
Biol Psychiatry 75:774-82. 2014....
- Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptorsAnthony 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...
- Alcohol-induced plasticity in the dynorphin/kappa-opioid receptor systemSunil 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...
- The effect of intermittent alcohol vapor or pulsatile heroin on somatic and negative affective indices during spontaneous withdrawal in Wistar ratsAngela 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...
- Conceptualizing withdrawal-induced escalation of alcohol self-administration as a learned, plasticity-dependent processBrendan 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....
- Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependenceBrendan 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....
- Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systemsAlexander 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...
- Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar ratsBrendan 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. ..
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