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Angiotensin converting enzyme inhibition as a potential therapeutic intervention for opioid relapse

Award Number: F31DA066289
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/01/2026
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Angiotensin converting enzyme inhibition as a potential therapeutic intervention for opioid relapse - PROJECT SUMMARY/ABSTRACT Opioid use disorders are chronic, relapsing brain conditions that have historically been difficult to treat due to a lack of effective treatments for reducing craving and relapse. Relapse increases the risk of fatal overdose, which makes it imperative to investigate the underlying mechanisms of relapse to inform the development of new therapeutic interventions. The nucleus accumbens (NAc) is a key brain region involved in relapse. The NAc contains two principal populations of medium spiny projection neurons: those that express the dopamine receptor Drd1 (D1-MSNs) and those that express the dopamine receptor Drd2 (D2-MSNs). Increased D1-MSN activity is canonically thought to drive drug responses, suggesting that selectively targeting increased excitatory input to D1-MSNs could represent a new therapeutic avenue for treating relapse. NAc D1-MSN activity can be selectively modulated through angiotensin-converting enzyme (ACE) inhibition. In the brain, ACE is highly enriched in NAc D1-MSNs and degrades the endogenous opioid peptide Met-enkephalin-Arg-Phe (MERF). Preventing MERF degradation through ACE inhibition decreases glutamate release onto D1-MSNs via activation of presynaptic mu opioid receptors. Our preliminary data indicate that systemic ACE inhibition via captopril in drinking water attenuates cue-induced reinstatement of fentanyl-seeking behavior in mice. Therefore, the goal of this proposal is to investigate whether ACE inhibition can counteract the maladaptive forms of NAc neuroplasticity that are normally associated with cue-induced reinstatement. To this end, Aim 1 will determine how systemic ACE inhibition impacts NAc MSN activity during opioid-seeking behavior. This will be done through measuring D1- and D2-MSN calcium responses during a test of cue-induced reinstatement, following 24 hours of oral captopril administration. Aim 2 will determine how systemic ACE inhibition impacts the strength of glutamatergic input to NAc MSNs following opioid-seeking behavior. This will be done through optogenetically evoking glutamatergic release from prefrontal cortex (PFC) axons in the NAc using ChrimsonR and recording the calcium responses from D1- and D2-MSNs before and after a test of cue-induced reinstatement. These evoked recordings will occur 24 hours after oral captopril administration. Aim 3 will use localized, intra-accumbal microinfusions of captopril to evaluate circuit-specific action. These will be performed prior to cue-induced reinstatement, in both the absence and presence of chemogenetic activation of the PFCàNAc projection to augment reinstatement. Completion of this fellowship will provide the PI with advanced technical training, leaving her well positioned for her long-term goal of becoming an independent researcher investigating the neurobiology of substance use disorders.


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 = $37,548 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Drug Use and Addiction Research Programs	001	1	5/13/2026	NEW	$0
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Drug Use and Addiction Research Programs	000	1	5/13/2026	NEW	$37,548
														Subtotal = $37,548

Grand Total All Awards = $37,548

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Angiotensin converting enzyme inhibition as a potential therapeutic intervention for opioid relapse

Award Number: F31DA066289

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/01/2026

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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