# Impact of prenatal opioid exposure on corticostriatal circuits that modulate alcohol-related behaviors

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2024 · $556,858

## Abstract

Project Summary
The number of children born to opioid-dependent mothers has increased over 300% in the past two decades.
As abstinence from opioids during pregnancy is not recommended, opioid medication replacement therapy, such
as methadone, represents the standard of care for pregnant women with opioid use disorder thus perpetuating
the birth of these opioid-exposed babies. Previous work has shown that prenatal opioid exposure predisposes
for future substance misuse. Given its widespread accessibility, alcohol is one of the most likely addictive sub-
stances that these prenatal opioid-exposed children will encounter. Due to the significant morbidity and mortality
associated with excessive alcohol drinking, it is critically important to understand how prenatal methadone ex-
posure (PME) predisposes these children for future problematic alcohol use and how alcohol interacts with PME
to produce differential behavioral responses to alcohol. To elucidate mechanisms related to how PME may pro-
duce enhanced alcohol-related behaviors, we developed and validated a mouse model of PME. Our model re-
capitulates many clinical features of prenatal opioid exposure, including producing neonatal opioid withdrawal.
Using our model, we find that PME increases alcohol drinking only in males, consistent with many clinical and
preclinical studies that show that males are more severely impacted by prenatal opioid exposure. Given the role
of the dorsal striatum brain region in modulating many aspects of alcohol drinking, we biochemically explored
the proteome of the dorsal striatum and found that PME had a greater effect on protein and protein phosphory-
lation expression in males than females, consistent with our drinking data. Pathway analyses of our proteomics
data implicated glutamate and long-term synaptic depression plasticity (LTD) in the dorsolateral striatum (DLS)
as being disrupted by PME. We further discovered that PME reduced dorsal striatal glutamate transmission and
disrupted LTD. Recent work from our laboratory demonstrates that alcohol induces glutamatergic synaptic plas-
ticity and disrupts LTD at anterior insular cortex inputs to the DLS (AICDLS synapses) in mice, but only in male
mice and this was associated with enhanced male alcohol drinking behavior. We reasoned that the male-specific,
PME-induced increase in binge-like alcohol consumption may utilize similar mechanisms as the male-specific,
alcohol-induced AICDLS synaptic changes that govern excessive alcohol consumption. We hypothesize that
PME produces synaptic adaptations exclusively in males that enhance AICDLS glutamatergic transmission
that in turn govern the elevated binge-like alcohol consumption seen in male, but not female PME mice. In this
project we will use a multidisciplinary approach combining home-cage binge drinking with brain slice electro-
physiology, dorsal striatal cell type reporter mice, quantitative synaptic proteomics, ultrastructural expansion mi-
croscopy, and wir...

## Key facts

- **NIH application ID:** 11139209
- **Project number:** 7R01AA030955-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Brady Atwood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $556,858
- **Award type:** 7
- **Project period:** 2024-06-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11139209

## Citation

> US National Institutes of Health, RePORTER application 11139209, Impact of prenatal opioid exposure on corticostriatal circuits that modulate alcohol-related behaviors (7R01AA030955-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11139209. Licensed CC0.

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