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. Despite recent efforts to curb use, 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 stop using. The aversive effects of dynorphin/KOR system activity have been linked to increased drug self-administration, and this system is known to cause reinstatement of drug seeking (heroin, cocaine, alcohol). While many reports of KOR dependent regulation of drug-seeking exist, there are are still few studies examining the role and mechanisms of stress-induced dynorphin-KOR activity on nicotine reinstatement. In our prior R01 grant cycle we sought to determine whether stress-induced reinstatement of nicotine preference is mediated through dynorphin and KOR, and mapped the critical brain regions where nicotine preference, and KOR and dynorphin mediated nicotine reinstatement occur. We determined that the amgydala, CA1 of hippocampus, and nucleus accumbens neurons are involved in nicotine place preference and reinstatement. We also established a reinstatement model of nicotine self-administration in mice that is KOR dependent. However, the neural networks, dynamics and circuit mechanisms responsible for KOR-dependent nicotine reinstatement are not understood. Understanding how dynorphinergic neural circuits and KOR cause nicotine reinstatement provides valuable and important insights and new therapeutic approaches to the treatment and prevention of stress-related nicotine relapse. Evidence from our prior cycle strongly suggests that amygdalar (BLA) and extended amgydala (BNST) circuits are the critical loci mediating the effects of KOR on reinstatement. However, while we isolated this region as important, the specific cell types, circuit dynamics, plasticity, and the temporal role of circuit in nicotine reinstatement is not known. In this cycle we propose to methodically dissect how activation of KOR, either by stress-induced dynorphin release, optogenetic/chemogenetic modulation of dynorphin release, or systemic administration of a selective KOR agonist, results in reinstatement of nicotine place preference in an excitatory BLA to BNST circuit. We propose the following Aims using an array of approaches: 1) determine the role of dynorphin/KOR activity in a BLA to BNST circuit as necessary and sufficient for stress-induced reinstatement of nicotine preference using retrograde viral rescue (?gain of function?), in vivo pharmacology, and conditional mouse genetics; 2) Use optogenetics and in vivo calcium imaging to determine the how dynorphin and KOR+ BLA to BNST circuits are activated by stress, and during reinstatement; 3) Using a mouse model of nicotine self-administration (IVSA), determine if KOR/Dynorphin in the BLA-BNST circuit is required for stress-induced reinstatement of nicotine IVSA. These studies test our central hypothesis that stress-induced reinstatement of nicotine seeking is mediated via dynamic dynorphin-KOR activation within discrete BLA and BNST cells, receptors, and circuits.

Public Health Relevance

Stress has protective and motivational components, yet repeated uncontrollable stress exposure increases the risks for mood disorders and nicotine addiction. Tobacco related deaths top 400,000 in US annually and the biological mechanisms underlying these effects need to be explored in order to provide for better treatments for nicotine addiction. Activation of the dynorphin / kappa opioid systems in the brain has been shown to encode the dysphoric and anxiogenic effects of stress and reinstates nicotine seeking, so the outcomes of the proposed studies would have direct impact on determining how stress modulates nicotine reward and offer potentially novel therapeutic strategies for nicotine addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1)
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Sorensen, Roger
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University of Washington
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