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DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE

Award Number: R37DA033396
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $426,589 )
2026	2026	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	000	14	4/1/2026	NON-COMPETING CONTINUATION	$426,589
														Subtotal = $426,589

Issue Date FY: 2025 ( Subtotal = $431,615 )
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	001	13	4/11/2025	NON-COMPETING CONTINUATION	$43,161
2025	2025	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	000	13	3/24/2025	NON-COMPETING CONTINUATION	$388,454
														Subtotal = $431,615

Issue Date FY: 2024 ( Subtotal = $436,533 )
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	001	12	4/25/2024	NON-COMPETING CONTINUATION	$43,652
2024	2024	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	000	12	3/21/2024	NON-COMPETING CONTINUATION	$392,881
2024	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	003	11	4/29/2024	EXTENSION WITH OR WITHOUT FUNDS	$386
2024	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	002	10	4/29/2024	NON-COMPETING CONTINUATION	-$386
														Subtotal = $436,533

Issue Date FY: 2023 ( Subtotal = $441,351 )
2023	2023	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	000	11	3/14/2023	EXTENSION WITH OR WITHOUT FUNDS	$441,351
														Subtotal = $441,351

Issue Date FY: 2022 ( Subtotal = $403,253 )
2022	2022	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	000	10	3/23/2022	NON-COMPETING CONTINUATION	$403,253
														Subtotal = $403,253

Issue Date FY: 2021 ( Subtotal = $409,183 )
2021	2021	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	000	9	3/29/2021	NON-COMPETING CONTINUATION	$409,183
														Subtotal = $409,183

Issue Date FY: 2020 ( Subtotal = $415,113 )
2020	2020	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	000	8	6/8/2020	NON-COMPETING CONTINUATION	$415,113
														Subtotal = $415,113

Issue Date FY: 2019 ( Subtotal = $449,745 )
2019	2019	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	005	7	3/19/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$455,674
2019	2019	UNIVERSITY OF WASHINGTON	4333 BROOKLYN AVE NE	SEATTLE	WA	98195	KING	USA	Drug Use and Addiction Research Programs	002	7	3/14/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$421,044
2019	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Drug Use and Addiction Research Programs	003	6	3/18/2019	COMPETING CONTINUATION	$28,701
2019	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Drug Use and Addiction Research Programs	001	6	3/14/2019	COMPETING CONTINUATION	$0
2019	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Drug Use and Addiction Research Programs	004	6	3/19/2019	COMPETING CONTINUATION	-$455,674
2019	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Drug Use and Addiction Research Programs	000	6	10/25/2018	COMPETING CONTINUATION	$0
														Subtotal = $449,745

Grand Total All Awards = $3,413,382

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DISSECTING DYNORPHIN-KAPPA OPIOID MEDIATED REINSTATEMENT OF NICOTINE PREFERENCE

Award Number: R37DA033396

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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