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Elucidating behavior and neural circuits underlying opioid addiction and dependence

Award Number: K99DA047413
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2022

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Elucidating behavior and neural circuits underlying opioid addiction and dependence - Project Summary/Abstract Prescription opioid addiction is a significant problem characterized by compulsive drug seeking, withdrawal and chronic relapse. Despite the growing impact of prescription opioids on public health, relatively few pre-clinical studies have investigated the neurobiological mechanisms underlying self-administration of oxycodone, a commonly prescribed medication. Neural circuits in the extended amygdala mediate emotional behaviors, and dysregulation of these reward and stress systems is a hallmark of drug dependence and withdrawal. Models of intravenous drug self-administration are a standard paradigm for investigating the reinforcing effects of drugs, and I have developed a model of oxycodone self-administration under extended access conditions (12 hours/day) that produces robust escalation of drug-seeking behavior and provides a translationally relevant model of opioid abuse. We hypothesize that escalation of oxycodone abuse and dependence are mediated by withdrawal-induced changes in neural signaling mechanisms, and that the manipulation of these underlying neural systems will attenuate the promotion of drug-seeking behavior. We will test this hypothesis using behavioral pharmacology, chemogenetics, and immunohistochemistry in a rat model of oxycodone self-administration under extended access conditions. My research training will be supervised by my mentors, Drs. Michael Taffe, Thomas Kash and Candice Contet, with additional support from Dr. Bryan Roth as consultant and Drs. Marisa Roberto, Kim Janda and Michael Forster as advisors for my career development. We have designed a multidisciplinary project that utilizes different experimental modalities that allow for behavioral, biochemical, and immunohistochemical investigation of oxycodone addiction and dependence. Precise characterization of KOR activation will be achieved through the use of the chemogenetic technology, designer receptors exclusively activated by designer drugs (DREADDs). We will employ neural circuit manipulations, specifically the inhibitory Gi-coupled kappa opioid receptor DREADD (KORD) in the central nucleus of the amygdala (CeA) GABAergic projection to paraventricular nucleus of the hypothalamus (PVN) to understand the effect of opioid-induced neuroadaptations mediating drug-seeking behavior. I will train in DREADD-based and immunohistochemical techniques to complement my experience in behavioral opioid pharmacology. These skills will be acquired during my K99 phase at The Scripps Research Institute and will be further implemented at my new institution during the R00 phase. My mentor team will help me establish these techniques in my independent laboratory to ensure experimental reproducibility. Collectively, this work will provide insight into the influence of kappa opioid receptor signaling in amygdalar pathways mediating opioid addiction and dependence-induced behavior.


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: 2023 ( Subtotal = -$189,388 )
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	8/16/2023	SUPPLEMENT FOR EXPANSION	-$136,322
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	2	8/16/2023	SUPPLEMENT FOR EXPANSION	-$53,066
														Subtotal = -$189,388

Issue Date FY: 2022 ( Subtotal = $234,963 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	2	6/29/2022	SUPPLEMENT FOR EXPANSION	$53,066
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	11/2/2021	SUPPLEMENT FOR EXPANSION	$181,897
														Subtotal = $234,963

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	6/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $161,358 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	2	8/17/2020	NON-COMPETING CONTINUATION	$161,358
														Subtotal = $161,358

Issue Date FY: 2019 ( Subtotal = $161,358 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	000	1	8/16/2019	NEW	$161,358
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Use and Addiction Research Programs	001	1	9/27/2019	NEW	$0
														Subtotal = $161,358

Grand Total All Awards = $368,291

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Elucidating behavior and neural circuits underlying opioid addiction and dependence

Award Number: K99DA047413

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2022

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