# Gao signaling mechanisms in the striatum

> **NIH NIH F32** · UNIVERSITY OF FLORIDA · 2022 · $16,487

## Abstract

Project Summary/Abstract
Opioid side effects including euphoria, tolerance and dependence limit clinical applications and have increasingly
contributed to fatal misuse. Opioid analgesia, reinforcement, and withdrawal are mediated by the μ-opioid
receptor, that is expressed throughout the reward circuit of the brain. Our long-term goal is to identify
mechanisms underlying and regulating μ-opioid receptor coupling to downstream pathways, and how these
respective pathways contribute to cellular and synaptic plasticity that promote addiction and dependence. In
addition to its acute neuromodulatory effects, cyclic AMP (cAMP) signaling is intimately involved in modulating
cellular, structural and synaptic plasticity from repeated opioid administration. Unlike the μ-opioid effectors Gαi
and Gβγ, our understanding of the mechanistic role of Gαo in transducing MOR signals is limited. Our lab and
others have supported a role of Gαo in coupling μ-opioid receptor activation to cAMP signaling using knockdown
approaches or by manipulating specific Regulators of G-Protein Signaling proteins. More recently, we have
identified changes in cAMP levels, opioid reinforcement behavior, and withdrawal phenotypes resulting from
striatal conditional Gαo knockout. We propose that these effects of Gαo deletion result from impaired MOR
coupling to AC, via modulation of Gβγ availability. In Aim 1, I will determine the contribution of Gαo to opioid-
evoked cAMP response dynamics of cultured striatal neurons using a genetically encoded optical cAMP
biosensor pioneered by our lab. This approach will be further applied in combination with optogenetic stimulation
of striatal inputs in brain slices to investigate how Gαo contributes to opioid induced adaptations of striatal
dopamine signal integration in an intact mesolimbic circuit. In Aim 2, I will use electrophysiology to determine
how Gαo contributes to opioid-induced adaptations that regulate striatal physiology and synaptic plasticity. In
Aim 3, I will determine the specific striatal circuits in which Gαo influences opioid reinforcement behaviors. These
studies will identify mechanistic contributions of Gαo to μ-opioid receptor signaling, subsequent adaptations that
modify striatal physiology, and how these effects ultimately influence opioid reinforcement behavior within
discrete striatal circuits. This research has the potential to identify new strategies for manipulating opioid
reinforcement for therapeutic applications, to address the ongoing epidemic of opioid abuse.

## Key facts

- **NIH application ID:** 10665127
- **Project number:** 6F32DA056216-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Cody William Kowalski
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $16,487
- **Award type:** 6
- **Project period:** 2022-09-16 → 2022-12-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10665127

## Citation

> US National Institutes of Health, RePORTER application 10665127, Gao signaling mechanisms in the striatum (6F32DA056216-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10665127. Licensed CC0.

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