Wednesday, April 2, 2025
4/2/2025
DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE - 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. While there are many reports of opioid receptor, specifically Kappa-opioid receptor dependent regulation of drug-seeking, there are are still few studies examining the circuit mechanisms of stress-induced endogenous opioid peptide/receptor activity on natural reward and nicotine reinstatement. In our first R01 cycle we determined that KORs within the basolateral amgydala, the CA1 of hippocampus, and nucleus accumbens neurons are involved in nicotine place preference and reinstatement. In the recent R37 cycle, we built substantially on our prior work, developing nicotine self-administration in mice so that we can use several cutting-edge methods to assess circuit function. Here we proposed and determined that while our lead candidate, BNST KORs were not required to reinstate nicotine seeking. We then in parallel turned to methodically examining, other stress-sensitive, opioid peptide and receptor expressing regions including the dorsal and ventral striatum, the BLA, the parabrachial nucleus, and the claustrum in order to determine where dynorphin/KOR circuits are engaged to regulate, potentiate and reinstate reward seeking behaviors. Evidence from our prior cycle, strongly suggests that amygdalar (BLA), dorsal striatum, nucleus accumbens and claustrum are among the likely critical loci mediating the effects of opioids, including KOR on stress induced reward seeking. However, while we isolated these regions as important for a variety of stress and reward seeking behavioral components, the specific cell types, circuit dynamics, plasticity, and the temporal role of these circuits in reward regulation, and nicotine IVSA is still not known. In this cycle we propose to methodically dissect how activation of KOR, either by stress-induced endogenous opioid release, optogenetic/chemogenetic modulation of opioid peptide release, viral CRISPR, or systemic administration of a selective opioid receptor agonists, results in altered natural reward seeking (action-outcome) models and in reinstatement of nicotine seeking in IVSA mouse models in an excitatory BLA to BNST circuit. We propose the following Aims: 1) determine the role of dynorphin/KOR activity in BLA-Striatal/Accumbens circuits as necessary - sufficient for regulating stress-induced reward seeking and reinstatement of nicotine self-administration using retrograde viral rescue (“gain of function”), in vivo pharmacology, and conditional mouse genetics; 2) Use optogenetics and in vivo 1p/2p calcium imaging, to determine the how dynorphin and KOR in these circuits are activated by stress and regulate reward seeking behaviors 3) Using a mouse model of nicotine self-administration (IVSA), determine if KOR/Dynorphin in the BLA-striatal circuits are 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 cells, receptors, and circuits. RELEVANCE (See instructions): Stress has protective and motivational components yet repeated uncontrollable stress exposure increases the risks for mood disorders and drug abuse, including opioids and nicotine. Tobacco related deaths top 400,000 in US annually and the biological mechanisms underlying these effects need to be explored in order to provide treatments for nicotine addiction. Activation of the opioid systems in brain has been shown to encode the dysphoric and anxiogenic effects of stress, regulates reward and causes relapse, so the outcomes of the proposed studies would have direct impact on determining how stress modulates reward and offer novel therapeutic strategies for nicotine addiction.
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