# Molecular and Cellular Profiling of the Habenulointerpeduncular Circuit in Opioid Tolerance and Withdrawal

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $601,612

## Abstract

ABSTRACT
The present crisis of opioid addiction in the United States highlights how an initial exposure to opioids, often
oxycodone, as a medical patient can lead to escalation of use, misuse and eventually addiction. Chronic
exposure to oxycodone produces tolerance to many of its effects, and it is this development of tolerance that
leads to taking increasingly higher doses and to withdrawal upon abstinence. Drug-induced adaptations in gene
expression and neuronal function are thought to underlie the development of tolerance and withdrawal, but the
mechanisms by which this occurs remain unclear. We have found that the habenula-interpeduncular nucleus
(IPN), which plays a prominent role in limiting nicotine intake and in nicotine withdrawal responds to chronic
nicotine by upregulating nitric oxide synthase 1 (NOS1), and that this same adaptation occurs in response to
chronic oxycodone exposure. Acute exposure to oxycodone is not sufficient to upregulate NOS1 in the IPN.
Using viral approaches, purification of tagged ribosomes followed by next gen sequencing and oral oxycodone
in the drinking water of adult male and female mice, we will examine gene expression in the IPN – both in the
presynaptic terminals and postsynaptic IPN neurons - and correlate neuronal calcium dynamics with intoxication
and withdrawal behavior. We will also examine the contribution of NOS1 to drug-induced changes in gene
expression in neuronal activity and axon terminals from the medial habenula within the interpeduncular nucleus.
Together these aims will establish a preclinical model of opioid tolerance that may provide a basis for evaluating
potential new therapeutics in the treatment of opioid use disorder.

## Key facts

- **NIH application ID:** 10979598
- **Project number:** 1R01DA059455-01A1
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jessica Ables
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $601,612
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10979598

## Citation

> US National Institutes of Health, RePORTER application 10979598, Molecular and Cellular Profiling of the Habenulointerpeduncular Circuit in Opioid Tolerance and Withdrawal (1R01DA059455-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10979598. Licensed CC0.

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