. A fundamental characteristic of alcohol use disorders is the loss of control over alcohol consumption that results in progressively escalating levels of alcohol use and facilitates the progression to alcohol-dependence. Given the comorbidity of alcohol dependence and disorders of affect such as de-pression is extremely high, it has been posited that self-medication of negative affective states contributes to continued excessive alcohol use and relapse. Furthermore, negative affective states produced by chronic alcohol exposure can influence the neurocircuitry of cognitive control systems to perpetuate further excessive alcohol use. Once that degree of dysregulation is reached, components of the dependence cycle serve to facilitate each other in a manner that is extremely deleterious to personal, familial and societal welfare. The principal investigator?s long-term goal is to identify effective therapeutic targets and strategies for the treatment of AUDs. The objective of this renewal application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in dynorphin (DYN) / kappa-opioid receptor (KOR) systems that occur in response to chronic alcohol exposure and contribute to maladaptive behavioral regulation in the form of maladaptive behavioral regulation. The central hypothesis is that the DYN / KOR system becomes progressively dysregulated in a manner that promotes the continued excessive consumption of alcohol and perpetuates the cycle of alcohol dependence. The rationale for the proposed studies is that identification of novel DYN / KOR- related treatment targets will enable the development of effective therapies designed to alleviate maladaptive behavioral regulation produced by dysphoria and alcohol dependence. This hypothesis will be tested by pursuing the following specific aims:
Aim #1 evaluates kappa-opioid receptor dysregulation within cortical nuclei during acute withdrawal within working memory and impulse control domains.
Aim #2 assesses the role of KORs in amygdalar nuclei in response to non-dependent dysphoria cues and alcohol-dependent withdrawal cue-induced maladaptive behavioral regulation using a combination of pharmacological and inducible genetic approaches. Animal models of self-administration, negative affective-like behavior, working memory and impulse control will serve as functional end-points to systematically investigate the mechanisms that contribute to maladaptive behavioral regulation in AUDs.
These specific aims will collectively help to identify important neuroadaptations in DYN / KOR systems that can promote the transition to, and perpetuation of, AUDs and will provide much needed information regarding the influence of DYN / KORs on the neurocircuitry maladaptive behavioral regulation. Such a contribution is significant because it will help develop personalized therapeutic targets to treat AUDs that focus on the removal of maladaptive phenotypes; 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 therapeutic strategies designed to alleviate negative emotional states and cognitive dysfunction that accompany alcohol dependence and withdrawal and persist into protracted abstinence to promote excessive alcohol consumption. The benefits of the current proposal are the combination of neuropsychopharmacological and genetic manipulations of kappa-opioid receptor systems that should provide a foundation for personalized therapeutics designed to reduce maladaptive behavioral regulation in alcohol dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA020394-10
Application #
9999385
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Egli, Mark
Project Start
2019-09-01
Project End
2023-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
10
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of South Florida
Department
Psychiatry
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33617
Erikson, Chloe M; Wei, Gengze; Walker, Brendan M (2018) Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis. Neuropharmacology 140:162-173
Sirohi, Sunil; Aldrich, Jane V; Walker, Brendan M (2016) Species differences in the effects of the ?-opioid receptor antagonist zyklophin. Alcohol 51:43-9
Kissler, Jessica L; Walker, Brendan M (2016) Dissociating Motivational From Physiological Withdrawal in Alcohol Dependence: Role of Central Amygdala ?-Opioid Receptors. Neuropsychopharmacology 41:560-7
Mann, Karl; Torup, Lars; Sørensen, Per et al. (2016) Nalmefene for the management of alcohol dependence: review on its pharmacology, mechanism of action and meta-analysis on its clinical efficacy. Eur Neuropsychopharmacol 26:1941-1949
Hipólito, Lucia; Wilson-Poe, Adrianne; Campos-Jurado, Yolanda et al. (2015) Inflammatory Pain Promotes Increased Opioid Self-Administration: Role of Dysregulated Ventral Tegmental Area ? Opioid Receptors. J Neurosci 35:12217-31
Sirohi, Sunil; Walker, Brendan M (2015) Maturational alterations in constitutive activity of medial prefrontal cortex kappa-opioid receptors in Wistar rats. J Neurochem 135:659-65
Kissler, Jessica L; Sirohi, Sunil; Reis, Daniel J et al. (2014) The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biol Psychiatry 75:774-82
Walker, Brendan M; Kissler, Jessica L (2013) Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats. Neuropsychopharmacology 38:2278-85
Berger, Anthony L; Williams, Angela M; McGinnis, Molly M et al. (2013) Affective cue-induced escalation of alcohol self-administration and increased 22-kHz ultrasonic vocalizations during alcohol withdrawal: role of kappa-opioid receptors. Neuropsychopharmacology 38:647-54
Walker, Brendan M; Valdez, Glenn R; McLaughlin, Jay P et al. (2012) Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. Alcohol 46:359-70

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