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Dopamine D2 Receptor Activation Dynamics and Function in Cocaine Use Disorder

Award Number: F31DA066150
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Dopamine D2 Receptor Activation Dynamics and Function in Cocaine Use Disorder - Project Summary Cocaine use disorder (CUD) poses a significant health concern with no FDA-approved pharmacotherapies. Cocaine’s ability to support reinforcement – and ultimately lead to addiction – depends on G protein-coupled dopamine receptors, especially those in the nucleus accumbens (NAc). Dopamine D2R receptors are located both on projections into the NAc as well as cells in the NAc, which has historically made it challenging to interrogate specific aspects of D2R function in vivo. Further, while receptor activation is often discussed as a binary process, emerging evidence shows that the kinetics of receptor activation play a key role in intracellular signaling. For D2R, agonism by dopamine rapidly recruits G protein-dependent signaling and then slowly engages non-canonical arrestin-dependent signaling. While these distinct pathways collectively modulate excitability and function, they can also operate independently of one another. To address these questions, we will leverage cutting-edge technology called membrane-anchored photoswitch (MP) which combines a membrane-anchored protein tag (M) and a light-controllable D2R agonist (P) to enable the cell-type selective targeting and activation of D2R with spatial and temporal control. We hypothesize for D2R the balance between G protein- and arrestin-dependent signaling is highly dependent on the magnitude and temporal kinetics of D2R activation and that G protein and arrestin-dependent pathways differently modulate CUD-associated behaviors. In Aim 1, we will apply MP in a combination of well plate reader-based kinetics assays and whole-cell patch clamp electrophysiology experiments to titrate the specific magnitude and duration of D2R activation and produce a panel that describes the kinetics of a variety of endpoints that reflect G protein- and arrestin-dependent signaling. In Aim 2, we will apply MP to titrate the specific magnitude and duration of D2R activation in rodent D2 medium spiny neurons (MSNs) and determine activation dynamic-dependent effects on (1) locomotor behavior and (2) positive reinforcement learning. We will then assess how chronic cocaine use alters activation dynamic-dependent effects by assessing behavioral responses to the same activation conditions in mice that have been chronically exposed to cocaine. Manipulating the specific timing and magnitude of D2R activation using MP will elucidate the relationships between D2R activation dynamics and function both in vitro and in vivo. The findings resulting from this proposal will contribute to our fundamental understanding of the role of D2R in the development and maintenance of CUD.


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 = $35,556 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Drug Use and Addiction Research Programs	001	1	6/3/2026	NEW	$0
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Drug Use and Addiction Research Programs	000	1	6/3/2026	NEW	$35,556
														Subtotal = $35,556

Grand Total All Awards = $35,556

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Dopamine D2 Receptor Activation Dynamics and Function in Cocaine Use Disorder

Award Number: F31DA066150

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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