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Reducing alcohol drinking with a nonmuscle myosin II small molecule in development

Award Number: R01AA032025
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Reducing alcohol drinking with a nonmuscle myosin II small molecule in development - PROJECT SUMMARY Many patients fail to respond or comply with current treatments for alcohol (ALC) use disorder (AUD). Relapse triggered by reminders of ALC use is a particular challenge to prevent, as the underlying memories exert a powerful motivational influence over behavior and represent a lifelong risk factor. These associations are supported by structural plasticity in dendritic spines, driven by learning-induced actin polymerization. Memory stability is subsequently achieved by arresting actin dynamics, stabilizing the cytoskeleton and making memories impervious to actin depolymerization within minutes. We have found that the actin cytoskeleton supporting memories for methamphetamine remains uniquely dynamic in the basolateral amygdala (BLA) long after training, enabling selective, retrieval-independent disruption of these memories and the motivation to seek drug after one 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. Genetic and pharmacologic targeting of NMII established it as a viable therapeutic target, and an NIH-funded medication development program for a clinically safe first-in-class NMII inhibitor (NMIIi) is underway, with an IND filing planned for Q3 of this year. Our labs were recently jointly funded by an MPI R21, through which we determined that systemic NMIIi reduces ALC self-administration in non-dependent rats when paired with a low priming dose of ALC to act as an unconditioned stimulus (US) that reactivates the association, making it labile to NMIIi-driven disruption of reconsolidation. The central hypothesis of the current proposal is that a single administration of an NMIIi will produce long-lasting disruption of ALC seeking and drinking in ALC-dependent animals, and that this effect will be mediated by the BLA. Specific Aim 1 will test the prediction that NMIIi paired with US reactivation reduces subsequent alcohol seeking and drinking in ALC-dependent rats. To help support clinical translation, the tolerability of co-administered ALC and NMIIi will be tested in a drug-drug-interaction study in the context of ALC dependence. Specific Aim 2 will test the prediction that combination therapy with NMIIi and FDA-approved AUD medications reduces ALC seeking and ALC self-administration in ALC-dependent animals. We will take advantage of the fact that there are multiple FDA-approved medications for AUD. Specific Aim 3 will test the prediction that the effects of NMIIi on ALC-associated memories, seeking and self- administration are mediated by structural plasticity changes in the BLA of ALC-dependent animals. The proposed work will characterize a new therapeutic approach for preventing relapse-like ALC seeking and drinking, will identify the locus of action and underlying structural plasticity for these effects, and will optimize drug administration parameters with an eye toward rapid translation through the use of a first-in-class compound whose NIH-funded development is on track for FDA approval.


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 = $567,832 )
2026	2026	LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER NEW ORLEANS	433 BOLIVAR ST RM 619	NEW ORLEANS	LA	70112	ORLEANS	USA	Alcohol Research Programs	000	1	5/27/2026	NEW	$567,832
														Subtotal = $567,832

Grand Total All Awards = $567,832

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Reducing alcohol drinking with a nonmuscle myosin II small molecule in development

Award Number: R01AA032025

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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