# Dopamine Circuit Regulation of Morphine Reinforcement Across the Opioid Exposure Cycle

> **NIH NIH R00** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $25,325

## Abstract

PROJECT SUMMARY
Pathological adaptions in the ventral tegmental area (VTA) dopamine system associated with chronic exposure
to opioids and opioid withdrawal can dysregulate responsivity to opioids and contextual cue associations. The
primary goal of this training proposal is to gain new skills in advanced computational techniques to delineate
how functionally diverse subpopulations of VTA dopamine neurons are regulated during morphine exposure
and the formation of morphine contextual associations in non-dependent and morphine-dependent mice.
Foundational findings have identified the intrinsic and synaptic (glutamatergic and GABAergic) adaptations that
VTA dopamine neurons undergo throughout acute and chronic opioid exposure. Yet, few studies have
accounted for the functional diversity of VTA dopamine neurons that mediate distinct aspects of cue-reward
processing and motivation. Dissociating the potential diversity of VTA dopamine responses in the development
of opioid dependence will help unravel the neural basis of the progression of opioid-use disorder. The Zweifel
lab has previously used a genetic approach to isolate functionally distinct subpopulations of dopamine neurons
that project to discrete regions of the nucleus accumbens (NAc). Corticotrophin releasing hormone receptor 1
(Crhr1)-Cre VTA dopamine neurons were found to selectively project to the NAc Core (VTACore) and
cholecystokinin (Cck)-Cre VTA dopamine neurons selectively project to the NAc medial Shell (VTAmShell). I
hypothesize that there exist projection-specific neural and behavioral correlates in response to morphine and
during the formation of morphine contextual associations in non-dependent and morphine-dependent mice. I
will investigate this using a systematic approach across three aims. For Aim 1 (K99), I will use behavioral
pharmacology and fiber photometry to determine whether VTACore and VTAmShell dopamine neurons
engage in uniform or differential dose-dependent neural activation dynamics in non-dependent and morphine
dependent mice. For Aim 2 (K99), I will use my skills in conditioned place preference and in vivo fiber
photometry to determine how the VTACore and VTAmShell neurons encode contextual associations to
morphine in non-dependent and morphine dependent mice. For Aim 3 (R00), I will determine the basis of these
pathological adaptations in VTA dopamine subpopulations by dissecting the role mu-opioid receptor (MOR)-
sensitive GABAergic inputs play in morphine contextual associations. During the K99 mentored phase, I will
gain new scientific training in Dr. Larry Zweifel’s laboratory, augmented by my advisory committee, in
computational analytical tools to analyze complex neurophysiological and behavioral data sets. I will also gain
new career development training from Dr. Zweifel, my advisory committee, and the MOSAIC UE5 program that
will facilitate my transition into a successful independent principal investigator in academia. Importantly, I will
continue...

## Key facts

- **NIH application ID:** 11074362
- **Project number:** 3R00DA054265-04S1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Barbara Juarez
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $25,325
- **Award type:** 3
- **Project period:** 2021-09-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11074362

## Citation

> US National Institutes of Health, RePORTER application 11074362, Dopamine Circuit Regulation of Morphine Reinforcement Across the Opioid Exposure Cycle (3R00DA054265-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11074362. Licensed CC0.

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