Role of Dynorphin and Kappa Opioid Receptors in Stress Effects on Ethanol Dependence-Related Escalated Drinking

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DESCRIPTION (provided by applicant): Alcohol dependence is a widespread public health concern with limited treatment options available. This chronic, relapsing disorder is characterized by periods of abstinence followed by a return to heavy use and can be modeled in rodents using a well-established chronic intermittent ethanol (CIE) exposure procedure. While stress is known to promote alcohol consumption and, in particular, trigger relapse, the influence of stress exposure on transition to excessive levels of drinking associated with dependence is less well understood. Our lab has shown that forced swim stress exposure accelerates the rate at which excessive drinking emerges in the CIE model of ethanol dependence and enhances the magnitude of escalated consumption in dependent but not nondependent subjects. The dynorphin/kappa opioid receptor (KOR) system is implicated in modulating both stress responses and ethanol consumption associated with dependence. Thus, it is plausible to suggest that the dynorphin/KOR system may play a role in this stress interaction with the CIE-drinking model. This research project is focused on examining the role of dynorphin/KOR activity in mediating the ability of stress exposure to facilitate and enhance escalation of drinkig in the mouse CIE model of ethanol dependence. The proposed studies will employ both systemic pharmacological and site-specific pharmacosynthetic approaches. For Aim 1, I will use our forced swim stress (FSS)-CIE-drinking paradigm to (1) assess whether administration of the novel, short-acting, selective KOR antagonist FP3FBZ attenuates stress facilitation of CIE-induced escalated drinking and (2) determine whether systemic administration of the KOR agonist U50,488 can substitute for and mimic the effects of FSS exposure in increasing ethanol drinking in CIE- exposed mice compared to nondependent controls. For Aim 2, I will use designer receptor technology (viral injection of Cre-dependent DREADDs) along with prodynorphin-IRES-Cre transgenic mice in the same FSS- CIE-drinking model to (1) determine whether 'silencing' dynorphin neurons (via activation of inhibitory DREADDs) in the central amygdala blocks stress facilitation of CIE-induced escalated drinking and (2) assess whether activation of dynorphin neurons (via excitatory DREADDs) in the central amygdala can substitute for and mimic the effects of stress exposure in enhancing ethanol intake in CIE-exposed mice compared to nondependent controls. Results from this project will advance our understanding of the neural mechanisms underlying the ability of stress to facilitate transition to excessive ethanol drinking associated with dependence, as well as characterize the potential for the KOR system to serve as a therapeutic target for treatment strategies for alcohol dependence.