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PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes

Award Number: R01DA050180
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes - Project Summary/Abstract Dysregulation of glutamate signaling is a core component of the pathological basis of drug addiction involving cocaine and many other substances. Recent progress in neuroscience and other fields clearly establishes that the molecular and cellular basis of glutamate-encoded signaling is vastly more complex than previously recognized. In particular, it is becoming increasingly evident that astrocytes, which are among the most abundant cells in the human brain, release glutamate to produce complex regulation over neural circuit activity. This novel form of glutamate-encoded intercellular signaling may be critical to understanding the pathological glutamate produced by long-term drug use since astrocytic glutamate release mechanisms, such as system xc- (Sxc), are altered by cocaine. While these discoveries raise numerous questions that may be essential in understanding glutamate signaling in the human brain, this proposal will focus on the question, how do neurons regulate glutamate release from astrocytes to control neural network activity and behaviors relevant to cocaine addiction. We will test the hypothesis that this is achieved by the actions of the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP), which we believe to be an unrecognized component of glutamate signaling in the nucleus accumbens (NAc). In support, we have found that A) PACAP mRNA is expressed in NAc afferents, B) PACAP receptors are expressed in NAc astrocytes and neurons projecting to the substantia nigra (SN) but not the ventral pallidum (VP), C) PACAP stimulates glutamate release from astrocytes by increasing the activity of system xc- (Sxc), D) PACAP application depresses eEPSCs in NAc medium spiny neurons (MSNs) projecting to the substantia nigra (SN) but not the ventral pallidum, and E) intra-NAc micro-infusion of PACAP blocks cocaine reinstatement. In this proposal, we will test the hypothesis that PACAP is a neuropeptide that regulates glutamate release from astrocytes and glutamate receptors on neurons to provide a novel form of pathway-specific regulation of NAc efferent pathways. In Aim 1, we will examine the molecular basis of PACAP-induced increases in Sxc activity and determine whether Sxc regulation is necessary for PACAP to depress eEPSCs in NAc-SN MSNs and block cocaine reinstatement. In this aim, we will also examine if PACAP increases glutamate from astrocytic release mechanisms other than Sxc. In Aim 2, we will examine the possibility that the form of astrocyte-neuron signaling triggered by PACAP require the regulation of neuronal glutamate receptors to produce the relevant changes in physiology that gate the output of NAc efferents and behavior. We will also explore whether PACAP alters presynaptic glutamate release. In Aim 3, we will investigate the role of endogenous PACAP to learn whether this neuropeptide is an unrecognized component of glutamate signaling in the NAc, and whether it is a key determinant of drug- seeking 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: 2025 ( Subtotal = $411,246 )
2025	2025	MARQUETTE UNIVERSITY	313 N 13TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	5	5/2/2025	NON-COMPETING CONTINUATION	$411,246
														Subtotal = $411,246

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	MARQUETTE UNIVERSITY	313 N 13TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	4	5/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $411,246 )
2023	2023	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	4	4/28/2023	NON-COMPETING CONTINUATION	$411,246
														Subtotal = $411,246

Issue Date FY: 2022 ( Subtotal = $411,246 )
2022	2022	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	3	4/21/2022	NON-COMPETING CONTINUATION	$411,246
														Subtotal = $411,246

Issue Date FY: 2021 ( Subtotal = $474,712 )
2021	2021	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	2	5/7/2021	NON-COMPETING CONTINUATION	$474,712
														Subtotal = $474,712

Issue Date FY: 2020 ( Subtotal = $515,431 )
2020	2020	MARQUETTE UNIVERSITY	915 W WISCONSIN AVE RM 175	MILWAUKEE	WI	53233	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	1	8/11/2020	NEW	$515,431
														Subtotal = $515,431

Grand Total All Awards = $2,223,881

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PACAP-Dependent Coordination of Glutamate Signaling between Neurons and Astrocytes

Award Number: R01DA050180

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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