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Molecular and Cellular Determinants of Tolerance to Second Generation Antipsychotics

Award Number: F31MH138072
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/01/2025
PERIOD OF PERFORMANCE END DATE: 10/31/2027

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Molecular and Cellular Determinants of Tolerance to Second Generation Antipsychotics - Contact PD/PI: lewis, elinor PROJECT SUMMARY Second generation antipsychotics (SGAs) are widely used clinical tools for the treatment of severe mental illness. However, their utility is highly variable, and they take weeks to become effective. The mechanisms behind this time course are not understood. SGAs are thought of as antagonists at the D2 dopamine receptor. Yet our recent work suggests that some SGAs function as arrestin-biased agonists at the less-characterized D3 dopamine receptor (D3R). Activation of the arrestin-3 pathway leads to degradation of D3R, potentially altering response to these drugs over time. I have generated preliminary data that shows mice grow tolerant to preclinical measures of SGA activity after chronic treatment of an arrestin-biased SGA. I hypothesize that D3R neurons are the locus of tolerance to select SGAs, and this tolerance is driven by decreased D3R membrane expression caused by arrestin-3 recruitment to D3R. I will use in vivo optical methods to assess changes in D3-neuron activity after chronic SGA treatment. I will also measure behavioral tolerance to SGA treatment in transgenic mice with altered abilities to degrade D3Rs and compare D3R levels using saturation binding and PET scans. This project will reveal mechanisms of tolerance to select SGAs at gross anatomy, cell- type, and protein levels. Project Summary/Abstract Page 6


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 = $33,538 )
2026	2026	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Mental Health Research Grants	001	2	1/30/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$33,538
2026	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	1	1/30/2026	NEW	$0
														Subtotal = $33,538

Issue Date FY: 2024 ( Subtotal = $42,520 )
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	000	1	8/28/2024	NEW	$42,520
2024	2024	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Mental Health Research Grants	001	1	8/28/2024	NEW	$0
														Subtotal = $42,520

Grand Total All Awards = $76,058

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Molecular and Cellular Determinants of Tolerance to Second Generation Antipsychotics

Award Number: F31MH138072

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/01/2025

PERIOD OF PERFORMANCE END DATE: 10/31/2027

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