# Validation of CD74 as a treatment target for methamphetamine use disorder

> **NIH NIH U18** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $199,362

## Abstract

Medication development for methamphetamine use disorder has historically focused on targeting
neurotransmitter systems with limited success, and there are currently no FDA-approved treatments for
methamphetamine use disorder. Emerging evidence demonstrates how immune factors can influence
addictive behaviors and contribute to substance use disorders. We have shown that our MHC class II
constructs bind to and downregulate the expression of CD74—the primary receptor for macrophage
migration inhibitory factor (MIF), a key inflammatory mediator in a number of diseases, including
methamphetamine use disorder. These constructs have therapeutic impact on cognitive function, drug-
seeking behavior, and inflammation in animal disease models. The primary objective of this U18
proposal is to conduct preclinical and in vitro drug validation experiments that evaluate CD74 as a
treatment target for methamphetamine use disorder. We hypothesize that blocking CD74 with our MHC
class II construct DRQ will promote abstinent-like behavior, improve cognitive function, and reduce
MIF/CD74 activation. Cd74 knockout mice and C57BL/6J control mice will be used to assess the effects
of methamphetamine and DRQ on cognitive function (e.g., working memory, attention). Sprague Dawley
rats will be used to test whether DRQ decreases operant methamphetamine self-administration, as
recently demonstrated in Lewis rats, thereby assuring data robustness. Preclinical in vitro target
assessment experiments will investigate the effects of methamphetamine and DRQ immunotherapy on
CNS inflammation. Focusing on brain areas critical for cognitive function and known to be damaged by
methamphetamine (i.e., striatum, hippocampus, and prefrontal cortex), we will evaluate whether DRQ
immunotherapy and/or CD74 deficiency: 1) inhibits inflammatory cell infiltration into the brain in
methamphetamine exposed animals, 2) alters the cell-surface expression of CD74 on peripheral and
CNS infiltrating myeloid cells, 3) blocks the binding of MIF to CD74, and 4) reduces MIF-stimulated
extracellular-signal-regulated kinase activation and the expression of inflammatory cytokines in the CD74
signaling cascade [e.g., monocyte chemoattractant protein-1 (MCP-1)]. In addition, we will use human in
vitro experiments to determine whether CD74 is important for pathogenic mechanisms in
methamphetamine addiction and to evaluate the feasibility of using CD74 (expression or function) as a
future biomarker for assessing DRQ immunotherapy treatment response. We expect that following the
completion of this one-year project, we will have definitive evidence to validate CD74 as a treatment
target and to support continued development of DRQ as a medication for methamphetamine use
disorder.

## Key facts

- **NIH application ID:** 10104408
- **Project number:** 1U18DA052351-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Marilyn Huckans
- **Activity code:** U18 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,362
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104408

## Citation

> US National Institutes of Health, RePORTER application 10104408, Validation of CD74 as a treatment target for methamphetamine use disorder (1U18DA052351-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10104408. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*