# Adolescent nicotine-induced enhancement of adult morphine reward: mediation by midbrain inhibitory circuits

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,036

## Abstract

Project Summary
 Opioid abuse remains one of the leading causes of preventable death in the United States1. A number of
elements contribute to this serious public health problem, with prior nicotine use being an important yet poorly
understood risk factor2. Nicotine is the main addictive component of tobacco products, including electronic
cigarettes, use of which is particularly prevalent among adolescents3. Despite compelling human epidemiological
studies linking adolescent nicotine use with future opioid abuse4, the underlying brain mechanisms remain
unclear. To address this scientific gap, this proposal investigates the neurobiological underpinnings linking
adolescent nicotine use with adult opioid abuse. Consistent with the literature5, our pilot behavioral data
demonstrate that mice treated with nicotine in adolescence show enhanced preference for a morphine-paired
context in the conditioned place preference (CPP) paradigm. As a potential neural substrate of this behavioral
interaction, the ventral tegmental area (VTA) is a heterogeneous midbrain nucleus, consisting of both dopamine
and GABA neurons, that is essential for reward processing and drug-related behaviors6-9. Extending this
literature, prior work from the Dani Lab demonstrated that nicotine exposure during the adolescent
developmental window produces a persistent change in VTA GABA neuron function that drives enhanced drug
seeking10. As evidence of such nicotine-induced neural adaptations in the VTA, our pilot electrophysiological
results revealed that the pharmacological effect of morphine on VTA GABA neurons (i.e. inhibition) is
paradoxically inverted (i.e. excitation) by adolescent nicotine treatment. How changes in GABA neuron function
relate to morphine reward remain unknown. For these reasons, this proposal tests the overarching hypothesis
that adolescent nicotine promotes adult morphine reward via altered morphine-induced excitability of VTA GABA
neurons. To test this hypothesis, my proposed project integrates ex vivo electrophysiology, in vivo chemogenetic
manipulations, and behavioral pharmacology to interrogate the role of VTA GABA neuron excitability in
adolescent nicotine-induced heightened morphine reward. Specifically, Aim 1 characterizes the effect of
adolescent nicotine on morphine-induced inhibitory signaling in the VTA. Aim 2 determines the role of aberrant
VTA GABA neuron activity, arising from adolescent nicotine exposure, in driving heightened morphine CPP.
Collectively, the results of this work will provide insight into the neural basis of nicotine-induced morphine abuse
liability and will further inform our understanding of midbrain plasticity in drug reward processing. This grant will
also provide crucial training for an aspiring independent scientist in an outstanding environment at the University
of Pennsylvania. In particular, this proposal represents a critical step in attaining the applicant’s career goal of
leading her own laboratory by combining a co...

## Key facts

- **NIH application ID:** 10156205
- **Project number:** 1F31DA053111-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ruthie Wittenberg
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156205

## Citation

> US National Institutes of Health, RePORTER application 10156205, Adolescent nicotine-induced enhancement of adult morphine reward: mediation by midbrain inhibitory circuits (1F31DA053111-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10156205. Licensed CC0.

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