# Mechanisms underlying addiction to cocaine after traumatic injury to the developing rodent brain

> **NIH NIH F32** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $38,098

## Abstract

Traumatic brain injury (TBI) is the leading cause of disability in children in the U.S., with the
highest risk reported in infants and young children (0-4 years old). There is a high prevalence of previous TBI
among cocaine users and an association between early age at time of TBI and cocaine use in adolescence.
Thus, early age at time of TBI is an important risk factor for development of addiction. Here I will propose to
study the relationship between injury to the rodent brain at postnatal day 21 (pnd21), an age that approximates
the toddler-aged child, neuroinflammation, and addiction to cocaine at adolescence. Cocaine and other
common drugs of abuse share a mechanistic link between increasing dopaminergic transmission in the
mesolimbic and mesocortical pathways and addictive behavior. Dopaminergic neurons originate in the ventral
tegmental area (VTA) of the midbrain, and project to the ventral striatum, including the nucleus accumbens
(NAc), and the prefrontal cortex (PFC). TBI at pnd21 reduces dopaminergic signaling in the striatum and VTA
at adulthood. Such a decreased dopaminergic state may increase the likelihood for sensitivity to addiction as a
mechanism to restore dopamine. What remains unclear is whether disruption to this signaling is evident during
the adolescent period, where there is an established high risk of substance abuse, and the extent to which
immune responses, expressed within in the acutely injured brain, alter long-term addictive behaviors. The
young brain shows a profound inflammatory response to TBI; we have found that interleukin-1 related signaling
is upregulated in cortical and subcortical structures within the first week after injury at pnd21. I will determine if
this upregulation likewise occurs in the reward pathways, a possibility that is reinforced by studies of TBI to the
adolescent brain where there is an upregulation of IL-1 cytokines and factors in the cortex and NAc. I
hypothesize that traumatic injury to the developing brain produces a robust early inflammatory
response in the reward pathway that enhances addictive liability to cocaine at adolescence. To test this
hypothesis, Aim 1 will determine if TBI at pnd21 leads to disruption of the reward pathway and enhanced
addictive liability of cocaine during subsequent brain development, utilizing a self-administration model of
cocaine addiction at adolescence and adulthood, and stereology to assess dopaminergic signaling in the
reward pathways. Aim 2 will evaluate inflammatory signaling in the reward pathway in the acutely injured brain,
and determine if IL-1 signaling contributes to addictive liability to cocaine at adolescence. Biochemical
techniques will be used to profile inflammation in the reward pathway after early age TBI. Brain-injured animals
will be acutely treated with an IL-1R antagonist or vehicle to assess impact of IL-1 on addictive liability at
adolescence. The data generated in these aims will broaden our understanding of age-dependent vuln...

## Key facts

- **NIH application ID:** 9913381
- **Project number:** 5F32NS108567-02
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Ramona E. von Leden
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $38,098
- **Award type:** 5
- **Project period:** 2019-05-06 → 2020-12-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913381

## Citation

> US National Institutes of Health, RePORTER application 9913381, Mechanisms underlying addiction to cocaine after traumatic injury to the developing rodent brain (5F32NS108567-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9913381. Licensed CC0.

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