# The mesointerpeduncular circuit in anxiety and nicotine withdrawal

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $335,000

## Abstract

Project Summary/Abstract
Chronic exposure to tobacco smoke accounts for ~6 million deaths per year making health complications from
smoking the primary cause of preventable mortality in the world. Current smoking cessation aids including
nicotine replacement therapy and medication that target nicotinic receptors are minimally effective. Thus, a
better understanding of brain regions, neural circuits, and neurotransmitter systems that underlie nicotine
withdrawal syndrome is needed to facilitate the development of new therapies for smoking cessation. While
dopaminergic (DAergic) neurons in the ventral tegmental area (VTA) that project to the nucleus accumbens are
critical for nicotine reward and reinforcement, recent studies have identified the habenulo-interpeduncular (Hb-
IPN) axis as a critical circuit in nicotine withdrawal symptoms. In particular, the IPN is implicated in increased
anxiety during nicotine withdrawal in rodents and receives inputs from cholinergic/glutamatergic medial
habenula neurons associated with affective behavior. Interestingly, we have identified a novel circuit
consisting of VTA neurons that project to the IPN, the mesointerpeduncular pathway. Our data indicate that
DA from VTA afferents may innervate the IPN to modulate neuronal activity and anxiety-like behavior via DA
receptor signaling. In addition, DA receptor expression in the IPN appears to be regulated by chronic nicotine
exposure. These observations provide the foundation for this application. We propose to test the hypothesis
that VTA DAergic neurons that project to the IPN modulate anxiety and are critical for increased anxiety during
nicotine withdrawal. In Aim 1, we propose to use molecular and biophysical approaches to test the hypothesis
that DA controls IPN neuronal activity through activation of DA receptors that are regulated by nicotine. In Aim
2, we will use pharmacology, optogenetics, and biophysical approaches to test the hypothesis that the IPN
receives DA input from the VTA. Finally, in Aim 3 we will use pharmacology, optogenetics, and behavior to
test the hypothesis that the mesointerpeduncular circuit modulates anxiety-like behavior at baseline and during
nicotine withdrawal. It is anticipated that understanding the role of the mesointerpeduncular circuit in anxiety
and nicotine withdrawal will provide novel strategies to alleviate anxiety and nicotine withdrawal symptoms.

## Key facts

- **NIH application ID:** 9854906
- **Project number:** 5R01DA041482-04
- **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:** 2020
- **Award amount:** $335,000
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9854906

## Citation

> US National Institutes of Health, RePORTER application 9854906, The mesointerpeduncular circuit in anxiety and nicotine withdrawal (5R01DA041482-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9854906. Licensed CC0.

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