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Therapeutic potential of M5 receptor targeting in stress-induced potentiation of drug reward

Award Number: R21DA064314
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Therapeutic potential of M5 receptor targeting in stress-induced potentiation of drug reward - Project Summary: Stress plays a central role in the development and persistence of substance use disorders (SUDs). Chronic or severe stress can lead to harmful drug use, and exposure to stressors often triggers relapse following prolonged abstinence. Understanding how stress induces neuroadaptations that increase vulnerability to drug use is crucial. Furthermore, stress must be incorporated into addiction models, particularly when evaluating novel therapeutic targets, as it drives profound molecular, cellular, and circuit-level changes that need to be appreciated for rational drug design. The muscarinic M5 receptor is highly expressed in midbrain dopamine neurons and enhances dopamine transmission in the nucleus accumbens. It has recently garnered interest as a therapeutic target for SUDs. Constitutive deletion or pharmacological inhibition of M5 receptors reduces drug self-administration. However, technical limitations have hindered direct examination of how M5 regulation of dopamine transmission influences drug-seeking behavior. Moreover, these studies have not included stress as a factor in their SUD models. Our preliminary data and prior studies show that repeated stress exposure enhances the hedonic evaluation of cocaine reward, measured using the cocaine conditioned place preference (CPP) assay. This same stress exposure disrupts M5 receptor-mediated regulation of dopamine transmission. Additionally, we found that selective deletion of M5 receptors from dopamine neurons potentiates cocaine CPP, mimicking the effects of stress, which contrasts with systemic M5 receptor disruption. Taken together, we hypothesize that stress-induced disruption of M5 signaling within the dopamine system increases subjective drug reward experience that can lead to vulnerability to substance use disorders. We propose that use of positive allosteric modulators directed toward M5 may mitigate the stress-induced potentiation of cocaine reward. We will test this hypothesis through two aims: Aim 1: Determine the effects of selective bi-directional manipulation of M5 receptors in dopamine neurons on cocaine conditioned place preference (CPP). Using transgenic and viral vector strategies, we will selectively manipulate M5 receptor expression in dopamine neurons in male and female mice. We will then assess how these manipulations influence context-cocaine Pavlovian associations and cocaine hedonic evaluation using CPP. Aim 2: Determine whether positive or negative allosteric modulation of M5 receptors can ameliorate the effects of stress on cocaine CPP. We will evaluate whether systemic treatment with M5 positive or negative allosteric modulators mitigates stress-induced potentiation of cocaine CPP when administered post-stress during the conditioning procedure.


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 = $423,500 )
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	3/23/2026	NEW	$423,500
														Subtotal = $423,500

Grand Total All Awards = $423,500

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Therapeutic potential of M5 receptor targeting in stress-induced potentiation of drug reward

Award Number: R21DA064314

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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