# Molecular Mechanisms of Susceptibility to Drug Use

> **NIH NIH K01** · UNIVERSITY OF MINNESOTA · 2021 · $163,057

## Abstract

PROJECT SUMMARY / ABSTRACT
The transition from drug use to abuse and, eventually, to dependence may be mediated by biological factors
that are present prior to drug use. Although chronic exposure to drugs of abuse is known to disrupt many
signaling pathways, little is known about the molecular mechanisms that mediate addiction susceptibility. There
is considerable interest in identifying early biomarkers for addiction susceptibility to improve addiction
prevention strategies. Most studies have been conducted in substance-dependent individuals where the
dissociation between ‘susceptibility’ and ‘consequence’ is ambiguous. I have recently identified a behavioral
phenotype in rats that reliably predicts future drug-taking behaviors and identified three proteins as potential
mediators of addiction susceptibility: sorting nexin 1 (SNX1), ryanodine receptor 2 (RYR2), and ataxin 2-like
(ATXN2L). These proteins are involved in intracellular trafficking, calcium signaling and cytoskeleton
reorganization, and have been previously linked to addiction. Precisely how differences in expression of these
proteins impact the signaling cascades underlying addiction susceptibility is not known. The overarching goal
of this proposal is to determine the functional and molecular role of proteins that mediate addiction
susceptibility and investigate how these factors are mechanistically linked to genetic and/or environmental
components of risk for addiction. To accomplish this goal, the proposed research will combine sophisticated
behavioral and computational assessments with viral, proteomic and bioinformatic approaches. In Aim 1 I will
use an inducible and reversible viral construct to bi-directionally manipulate expression of SNX1, RYR2, and
ATXN2L and also determine how changes in expression of SNX1, RYR2, and ATXN2L alter
methamphetamine self-administration and protein signaling mechanisms. In Aim 2 I will determine if variation
in the expression of SNX1, RYR2, and ATXN2L is altered in a model of genetic addiction susceptibility and is
associated with increased addiction risk. In Aim 3 I will determine if variation in expression of SNX1, RYR2,
and ATXN2L is altered in a model of environmental addiction susceptibility and is associated with increased
addiction risk. Completion of these aims will generate new insights into the signaling mechanisms of addiction
susceptibility that could identify early biological markers of risk for addiction and improve current strategies for
addiction prevention. The Principal Investigator will receive mentorship and technical training in viral and
proteomic technologies by experts in cell signaling and cellular mechanisms, and viral technologies in
motivated behaviors. Yale University and the Department Psychiatry provide exceptional facilities and
resources for completing the proposed experiments, as well as having an exceptional reputation and track
record for mentoring and transitioning early-stage investigators in to independen...

## Key facts

- **NIH application ID:** 10215467
- **Project number:** 5K01DA051598-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Stephanie Mary Groman
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $163,057
- **Award type:** 5
- **Project period:** 2021-01-04 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10215467

## Citation

> US National Institutes of Health, RePORTER application 10215467, Molecular Mechanisms of Susceptibility to Drug Use (5K01DA051598-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10215467. Licensed CC0.

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