# Determining if Activity in Specific Lateral Habenula Output Pathways Motivates Avoidance of Synthetic Opioid Withdrawal or Cue Induced Reinstatement

> **NIH NIH K99** · UNIVERSITY OF WASHINGTON · 2021 · $174,528

## Abstract

Project Summary
Opioid abuse has reached epidemic proportions in the United States and is responsible for more than 40,000
overdose deaths each year 1. In particular, synthetic opioid addiction has proven to be extremely difficult to
combat, in part because it generates powerful opponent processes in the user. Each dose of synthetic opioid
produces rapid and potent euphoria that is strongly associated to drug cues, while withdrawal and abstinence
from synthetic opioids induce severe distress. Avoidance of withdrawal and subsequent exposure to drug cues
are key deterrents to long-term abstinence. The Lateral Habenula (LHb) is an exciting target for studying
neuronal facilitation of relapse, as LHb activity is correlated with both stress evasion and the encoding of
motivational value 6. LHb activity during acute withdrawal may motivate relapse via stress avoidance
mechanisms, while during abstinence cues that are normally paired with drugs go unrewarded, inducing activity
in the LHb. This activity may motivate drug seeking via a process akin to reward prediction error. Under the
primary mentorship of Drs. John Neumaier, Michael Bruchas, Paul Phillips, and Charles Chavkin, this K99/R00
Pathway to Independence award will allow me to obtain training in cutting edge in-vivo calcium imaging and
optogenetics, and oral self-administration model development. This training will allow me to elucidate the roles
of the major LHb output pathways in motivating avoidance of fentanyl withdrawal and cued reinstatement. During
the mentored phase of this grant I will be trained to use GCaMP6-based in-vivo calcium imaging to record LHb
neurons that project specifically to the ventral tegmental area (VTA), the rostromedial tegmentum (RMTg), or the
dorsal raphe nucleus (DRN) during naloxone-precipitated withdrawal, conditioned place aversion testing, and
fentanyl reinstatement. I will also be trained to combine in-vivo calcium imaging with red-shifted optogenetic
inhibition in order to leverage simultaneous circuit imaging and recording, and test causal relationships between
neural pathway activity and behavior. Finally, I will be trained in novel oral fentanyl self-administration (SA) model
development, which will be invaluable to my independent research career as a behavioral neuroscientist. During
the independent phase of the award, I will combine this training with my prior expertise to determine if activity in
each LHb pathway is necessary for expression of withdrawal related negative affect, withdrawal induced CPA,
or cued reinstatement to fentanyl seeking. I will do so by simultaneously inhibiting LHb projections and recording
from each LHb target region (VTA, RMTg, or DRN) to determine the effect of inhibition on behavior and
monoaminergic nucleus activity. In summary, the research proposed in this Pathway to Independence Award
will elucidate the role of individual LHb pathways in motivating avoidance of withdrawal and cued reinstatement,
as well as their role i...

## Key facts

- **NIH application ID:** 10300262
- **Project number:** 1K99DA052571-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Kevin R. Coffey
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $174,528
- **Award type:** 1
- **Project period:** 2021-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10300262

## Citation

> US National Institutes of Health, RePORTER application 10300262, Determining if Activity in Specific Lateral Habenula Output Pathways Motivates Avoidance of Synthetic Opioid Withdrawal or Cue Induced Reinstatement (1K99DA052571-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10300262. Licensed CC0.

---

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