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Involvement of Gq Signaling in the Mobilization of 2-Arachidonoylglycerol by Corticosterone in the Prefrontal Cortex

Award Number: F31DA060687
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Involvement of Gq Signaling in the Mobilization of 2-Arachidonoylglycerol by Corticosterone in the Prefrontal Cortex - Substance use disorder (SUD) affects 8.5% of the United States population with many individuals who go through cycles of abstinence and then relapse to drug taking. Stress is one of many factors that can potentiate drug relapse and a key neural circuit involved in stress-potentiated drug seeking behavior involves neurons in the prefrontal cortex (PFC) that project to the nucleus accumbens (NAc). Emerging evidence has shown that CORT can regulate the endocannabinoid signaling system in a rapid and glucocorticoid receptor independent manner. Previous studies from our group indicate that CORT rapidly mobilizes 2-arachidonoylglycerol (2-AG) in medial prefrontal cortex (mPFC) pyramidal neurons which activates cannabinoid 1 receptors (CB1Rs) on GABAergic axons to inhibit GABA release in a retrograde manner. We hypothesize that this effect of CORT decreases inhibitory synaptic transmission, thus increasing excitability of neurons in the mPFC that comprise output pathways that mediate motivation and promote cocaine seeking in abstinent rats. However, the precise mechanism through which CORT rapidly mobilizes 2-AG is unclear. The purpose of this research project is to examine the overall hypothesis that Gq-coupled GPCR signaling is required for the rapid CORT mobilization of 2-AG in the PFC and that this mechanism underlies CORT-dependent effects of stress- potentiated relapse in substance use disorder. To test this hypothesis, I will utilize ex vivo whole cell recordings, a self-administration/cocaine seeking paradigm, an eCBGRAB2.0 approach, and fiber photometry. In Aim 1, I will conduct ex vivo whole cell recordings of PFC pyramidal neurons to assess GABAergic neurotransmission and photometry in brain slices following eCBGRAB2.0 expression to directly measure 2-AG release to examine the mechanism by which CORT recruits endocannabinoid signaling at this synapse. I will examine the requirement for CORT induced Gq-mediated signaling to increase 2-AG synthesis. In Aim 2, I will study rats in a self-administration/cocaine seeking paradigm alongside fiber photometry following the expression of an eCBGRAB2.0 biosensor to study endocannabinoid concentrations within the mPFC during CORT-potentiated reinstatement of drug seeking. Successful completion of these aims will enhance our understanding of the mechanism by which CORT mobilizes endocannabinoid signaling and increase our ability to design therapeutic interventions towards SUDs. The associated fellowship training plan aligns with these research aims and leverages my development as a research scientist and interactions with my mentorship team to enhance my technical, intellectual, and professional development to support my goal of becoming an independent investigator working in an academic environment. The environment in the Department of Pharmacology at the Medical College of Wisconsin has high-quality instrumentation for the proposed studies and provides supportive faculty towards my future goals to obtain my PhD and become an independent researcher.


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 = $49,538 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Drug Use and Addiction Research Programs	001	2	7/22/2025	NON-COMPETING CONTINUATION	$564
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	2	3/21/2025	NON-COMPETING CONTINUATION	$48,974
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Drug Use and Addiction Research Programs	001	1	3/14/2024	NEW	$0
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Drug Use and Addiction Research Programs	000	1	3/14/2024	NEW	$47,694
2024	2024	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Drug Use and Addiction Research Programs	002	1	4/30/2024	NEW	$1,280
														Subtotal = $48,974

Grand Total All Awards = $98,512

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Involvement of Gq Signaling in the Mobilization of 2-Arachidonoylglycerol by Corticosterone in the Prefrontal Cortex

Award Number: F31DA060687

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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