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Myosin II regulation of actin dynamics and the selective vulnerability of methamphetamine- and opioid-associated memory

Award Number: R01DA049544
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY There are no pharmacotherapies for stimulant abuse, including methamphetamine (METH) and relapse rates are high. Relapse triggered by reminders of drug use is a particular challenge to prevent, as the underlying memories exert a powerful motivational influence over behavior and represent a lifelong relapse risk factor. Learning is supported by structural plasticity in dendritic spines, driven by training-induced actin polymer- ization. Memory stability is subsequently achieved by arresting actin dynamics, stabilizing the cytoskeleton. As a result, memory is impervious to actin depolymerization within minutes of learning. However, prior work in the lab discovered that the actin cytoskeleton supporting METH memories remains uniquely dynamic in the amygdala long after training. This enables selective, retrieval-independent disruption of METH-associated memories and drug seeking with a single administration of an actin depolymerizer. Because actin’s critical roles in the body limit its therapeutic potential, focus shifted to nonmuscle myosin II (NMII), a direct driver of learning-stimulated actin polymerization in spines. The effect of NMII inhibition is specific to the amygdala and METH. Indeed, NMII inhibition has no effect on METH memories when other regions of the drug-memory neural circuit are targeted and there is no similar retrieval-independent effect on memories for fear, food reward or other drugs of abuse, including opioids. Genetic and pharmacologic targeting of NMII established it is a viable therapeutic target and an NIH-funded medication development project for a clinically safe NMII inhibitor is underway (UH3 NS096833). However, fundamental knowledge needed to understand and further leverage this specificity is lacking. This will be addressed through the central hypothesis in this new project: that METH-associated memories are uniquely supported in the amygdala by NMII, leaving those memories selectively vulnerable to disruption long after learning, even when other associative learning is introduced. The focus of this application is two-fold: (1) The key mechanistic question regarding the specific requirement of the amgydala, actin-NMII and METH for selective memory storage disruption will be addressed. For this, the impact of METH-related neuromodulators (Aim 1), as well as NMII phosphorylation and interacting partners (Aim 2) will be studied on NMII-dependent BLA synaptic actin dynamics and METH-associated memory, with a focus on factors that are unique to METH and the BLA. Once identified, the mechanism(s) responsible could be harnessed to render relapse-inducing memories for other drugs of abuse vulnerable to disruption. (2) Because most individuals with METH use disorder use multiple substances, including opioids, it is necessary to determine the impact of polydrug administration on METH memory susceptibility to NMII inhibition. Preliminary data indicate that METH confers susceptibility to previously impervious opioid associations. Technically innovative approaches will be employed throughout the project, spanning from single synapse manipulations in live tissue slices to memory-based self-administration studies.


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: 2024 ( Subtotal = $649,455 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Abuse and Addiction Research Programs	000	6	11/14/2023	NON-COMPETING CONTINUATION	$649,455
														Subtotal = $649,455

Issue Date FY: 2023 ( Subtotal = $721,617 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Abuse and Addiction Research Programs	003	5	1/18/2023	NON-COMPETING CONTINUATION	$72,162
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Abuse and Addiction Research Programs	000	5	11/25/2022	NON-COMPETING CONTINUATION	$649,455
2023	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Abuse and Addiction Research Programs	002	4	1/3/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$38,556
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	001	2	1/3/2023	NON-COMPETING CONTINUATION	-$38,556
														Subtotal = $721,617

Issue Date FY: 2022 ( Subtotal = $721,617 )
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	001	3	3/24/2022	NON-COMPETING CONTINUATION	$72,162
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Drug Abuse and Addiction Research Programs	004	4	4/11/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$721,617
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	002	3	3/25/2022	NON-COMPETING CONTINUATION	$0
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	000	3	12/1/2021	NON-COMPETING CONTINUATION	$649,455
2022	2022	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	003	3	4/11/2022	NON-COMPETING CONTINUATION	-$721,617
														Subtotal = $721,617

Issue Date FY: 2021 ( Subtotal = $721,617 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	000	2	11/19/2020	NON-COMPETING CONTINUATION	$649,455
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	001	2	2/19/2021	NON-COMPETING CONTINUATION	$72,162
														Subtotal = $721,617

Issue Date FY: 2020 ( Subtotal = $721,617 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Drug Abuse and Addiction Research Programs	000	1	12/13/2019	NEW	$721,617
														Subtotal = $721,617

Grand Total All Awards = $3,535,923

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Myosin II regulation of actin dynamics and the selective vulnerability of methamphetamine- and opioid-associated memory

Award Number: R01DA049544

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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