# Targeting gut brain-signaling to reduce cocaine seeking behaviors

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $79,058

## Abstract

Project Summary
Pathological substance use disorders are devastating psychiatric conditions that lead to patterns of increasing
and out of control substance use. These disorders account for significant morbidity and mortality amongst
patients and inflict untold costs on their families and loved ones as well as society at large. Of these disorders,
pathological use of cocaine and other psychostimulants accounts for a significant proportion of morbidity and
mortality. Despite tremendous advances in understanding of the neurobiology of stimulant use disorders, there
are no FDA-approved pharmacotherapies for stimulant use disorders. In treating patients with stimulant use
disorder, the largest hurdle to overcome is in preventing drug relapse. In recent years there has been a
growing understanding that a number of systems outside of the brain can play a critical role in shaping brain
and behavior. Among these is the resident population of bacteria in the intestinal tract – collectively referred to
as the gut microbiome. Extensive research now demonstrates that changes in the gut microbiome play a
critical role in both normal brain function, as well as in the development of pathological states. In our own lab
we have previously published that acute depletion of the microbiome can alter the rewarding effects of cocaine
and affect gene expression changes in the brain. More recently, we have begun investigating how depleting
the microbiome with antibiotics affects the persistence of behavioral and brain gene expression changes in
animal models of relapse. We find that animals that lack a complex microbiome have increased cocaine
seeking behaviors after a prolonged period of abstinence. Genome-wide RNA-sequencing analyses
demonstrate that these animals have robust changes in gene expression in important striatal gene networks
that affect synaptic plasticity and behavior. Additional analyses demonstrate epigenetic changes in chromatin
structure. Importantly, behavioral and molecular effects of microbiome depletion can be largely reversed by
replenishment of specific bacterially derived small molecules. In this grant we will work in two comprehensive
Aims to clarify the specificity and mechanisms of these effects and will work to further targeting the gut
microbiome and its molecular byproducts. Aim 1 will define temporal specificity of microbiome depletion effects
on drug seeking behaviors with targeted microbiome depletions and reconstitutions at different phases of
behavior. Behavioral studies will be coupled with molecular analyses of synaptic plasticity related
transcriptional and epigenetic effects. Additional analyses of microbiome composition will define bacterial
populations associated with increased drug seeking. Aim 2 will further clarify the role of individual microbiome-
derived small molecules in driving these behavioral and molecular changes. These studies will provide critical
mechanistic insight into gut-brain signaling in a model of cocaine...

## Key facts

- **NIH application ID:** 11087232
- **Project number:** 3R01DA056592-02S1
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Drew Kiraly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $79,058
- **Award type:** 3
- **Project period:** 2023-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11087232

## Citation

> US National Institutes of Health, RePORTER application 11087232, Targeting gut brain-signaling to reduce cocaine seeking behaviors (3R01DA056592-02S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11087232. Licensed CC0.

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