# Insula Circuitry and Compulsive Alcohol Drinking: AD Supplement

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $332,136

## Abstract

Abstract
Alzheimer’s Disease (AD) is the most common human dementia, which extracts substantial emotional and
economic costs on AD patients and their caregivers. Thus, there is considerable interest in mechanisms which
reflect treatment targets, including for cognitive and emotional disruptions. Part of the Parent R01 for this
Supplement focuses on the central importance of Locus Coeruleus (LC) and norepinephrine (NEPI) receptors in
compulsion-like alcohol drinking, where intake continues despite known negative consequences. The LC/NEPI
system is a key regulator of cognition and emotion, especially under challenge or stress, and one long-term goal
is to develop sufficient mechanistic understanding of the LC/NEPI to provide pharmacotherapies that disrupt
compulsion-like and anxiety-driven aspects of addiction.
 Considerable evidence suggests that AD patients have a disrupted LC/NEPI system. There is partial loss
of LC NEPI cells and some compensatory upregulation of NEPI release, and many AD LC/NEPI changes
correlating with dementia severity. Also, aggression, a common AD symptom, is reduced by inhibiting several
NEPI receptors (alpha1 or beta). Our R01 work finds that alpha1 or beta inhibition is particularly effective against
compulsion-like drinking, with others showing similar results for excessive drinking with dependence, suggesting
important LC/NEPI mechanistic similarities between AD cognitive/emotional dysregulation and uncontrolled
addictive drives. However, there is also evidence for hypoactivity of some aspects of the LC/NEPI system. To
better understand the LC/NEPI impact during AD, it is critically important to understand the actually activity
level of LC NEPI neurons. We hypothesize that AD-related disruptions of LC neurons can produce
hyperactivity or hypoactivity, which could vary across AD development (possibly switching from hyper
early to hype later) and across individuals.
 To address this central question of actual LC cell activity, we seed dbh-Cre mouse LC with human
AD-tau brain material (or non-AD control) and, after 2.5-3 or 5-6 months, examine LC cell activity using the
cutting-edge fiber photometry. Since LC cells fire tonically, we will inhibit LC cells with clonidine and local infusion
of a strong inhibitor (lidocaine), where drop in activity gives strong indication of basal LC activity. We also
examine LC cells and NEPI/metabolite levels to better understand LC disruption across AD-like development.
 These studies will allow us to initiate a complementary line of research for the lab, including an R01
submission (based from Supplement studies) to examine how altered activity of LC cells (or LC terminals) in a
given individual, and at different times of AD development, relates to cognitive and affective behavioral
disruptions. Our association with the Indiana University Alzheimer’s Center and Stark Model-AD (in the same
building as my lab) will allow us to be immediate contributors to the AD research field and will gr...

## Key facts

- **NIH application ID:** 10126606
- **Project number:** 3R01AA024109-06S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Frederic Woodward Hopf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $332,136
- **Award type:** 3
- **Project period:** 2016-06-08 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10126606

## Citation

> US National Institutes of Health, RePORTER application 10126606, Insula Circuitry and Compulsive Alcohol Drinking: AD Supplement (3R01AA024109-06S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10126606. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*