# Interpeduncular circuitry in stress-responsive behaviors and nicotine dependence

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $471,980

## Abstract

Project Summary/Abstract
Stress is a risk factor for the development of addiction, as well as for relapse in abstinent drug users. Over
recent years, it is becoming increasingly clear that dopaminergic circuitry originating in the ventral tegmental
area, which is the most well studied in the context of addiction, is also critical for the behavioral response to
stress suggesting an interaction between stress and addiction. Recent studies have determined that the medial
habenulo-interpeduncular (MHb-IPN) axis is an essential circuit in the pathophysiology of drugs of abuse,
especially nicotine. Specifically, this circuit controls nicotine intake in rodent models, while also mediating the
acute aversive effects of high doses of nicotine. In addition, the IPN has been implicated as an important hub
for anxiety during nicotine withdrawal. Specifically, the stress neuropeptide, CRF is released and activates
CRF1 receptors in the IPN triggering anxiety suggesting that the IPN is a component of the extrahypothalamic
stress network in the brain. However, how the IPN responds to stress in vivo and if/how the IPN may contribute
stress-induced behaviors is unknown. Thus, the goal of this application is to test the hypothesis that the IPN is
a stress-responsive brain area and a critical mediator of stress-induced behaviors that becomes dysregulated
in nicotine-dependence to drive stress effects on nicotine dependence-associated behaviors. In Aim 1, we will
combine GCaMP expression with fiber photometry and optogenetics to test if stress-activation of IPN
GABAergic neurons is critical for stress-induced behaviors. Aim 2 will also combine GCaMP expression with
fiber photometry and test the hypothesis that nicotine dysregulates the response to stress in the IPN to drive
relapse. Finally, Aim 3 will test the hypothesis that stressors engage dopaminergic pathways by activating IPN
neurons that project to the lateral dorsal tegmentum. It is anticipated that elucidating circuitry and neuronal
mechanisms underlying stress-induced behaviors in an understudied brain region that is emerging as a critical
node for nicotine dependence should yield great insights into behaviors associated with addiction and set the
foundation for therapeutic strategies for new treatment.

## Key facts

- **NIH application ID:** 10873159
- **Project number:** 5R01DA041482-08
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** ANDREW R TAPPER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $471,980
- **Award type:** 5
- **Project period:** 2017-05-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873159

## Citation

> US National Institutes of Health, RePORTER application 10873159, Interpeduncular circuitry in stress-responsive behaviors and nicotine dependence (5R01DA041482-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10873159. Licensed CC0.

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