Dopamine D2 receptor activation dynamics and function in cocaine use disorder
Active Project Grant Awarded Last action
- Award ID
- F31DA066150
- Recipient
-
Vanderbilt University UEI GTNBNWXJ12D5
- Awarding agency
-
National Institute on Drug Abuse
National Institutes of Health, Department of Health and Human Services
- Obligated
- $71,112
Award facts
- Assistance listing
- 93.279 Drug Use and Addiction Research Programs
- Completion date 0% complete
- Originally
- Place of performance
- Nashville, TN 37203, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $35,556 | |
| Amendment | $0 | |
| Original award | $35,556 |
Quick answers
Who received award F31DA066150?
F31DA066150 was awarded to Vanderbilt University by National Institute on Drug Abuse (National Institutes of Health) on November 30, 2026.
How much is award F31DA066150 worth?
$71,112 has been obligated on F31DA066150.
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