# Molecular and Cellular Determinants of Tolerance to Second Generation Antipsychotics

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2024 · $42,520

## Abstract

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.

## Key facts

- **NIH application ID:** 11071688
- **Project number:** 1F31MH138072-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Elinor Lewis
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,520
- **Award type:** 1
- **Project period:** 2024-11-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11071688

## Citation

> US National Institutes of Health, RePORTER application 11071688, Molecular and Cellular Determinants of Tolerance to Second Generation Antipsychotics (1F31MH138072-01A1). Retrieved via MORVS 2026-10-28 from https://api.morvs.ai/grant/nih/11071688. Licensed CC0.

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