# Role of lateral habenula in methamphetamine TAAR1-mediated synaptic plasticity and aversion

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $545,655

## Abstract

PROJECT SUMMARY
Considerable research has focused on drug use disorders as motivational disorders involving inherent or drug-
induced reward pathway function. However, the focus of this application is on opposing aversive effects of
methamphetamine (MA) that may curb its use, which have been little studied. The Richards (Phillips)
laboratory identified the trace amine associated receptor 1 (TAAR1) as a critical target impacting MA-induced
aversion. TAAR1 is an intracellularly located G protein-coupled receptor. MA gains access to TAAR1 only if it
is transported into the cell. This occurs via extracellular membrane transporters, such as dopamine and
serotonin transporters, DAT and SERT, respectively. We propose that TAAR1 activation by MA in dopamine
and serotonin neurons is responsible for MA-induced aversion and that monoaminergic circuit interactions with
the lateral habenula (LHb) are of particular importance. The overarching goal of the studies proposed in this
application is to understand the monoaminergic neuron-LHb interactions responsible for the experience of MA-
induced aversion via TAAR1 that may reduce risk for MA use. Our preliminary data show that MA activates
lateral habenula (LHb) neurons, specifically in mice with functional TAAR1. The studies in Aim 1 will use slice
electrophysiology to examine the TAAR1-dependent effects of MA in ventral tegmental area dopamine and
dorsal raphe serotonin neurons, comparing slices from wildtype and CRISPRed knock-in mice, mice that have
functional vs. nonfunctional TAAR1, respectively. Aim 1 studies will also use optogenetic stimulation to
examine the effects of MA on glutamatergic synapses from the LHb. Based on our published findings,
functional behavioral studies in this aim will examine the role of a glutamate receptor subunit, GluN2B, on MA
aversion and intake. Aim 2 will perform behavioral studies focused on the LHb, which has been shown to
mediate other types of aversion, has not been studied for MA aversion. We will ablate the LHb in mice with
and without functional TAAR1 and study the impact on MA aversion and intake. Finally, Aim 3 studies will use
a retrograde tracer to identify the LHb neurons that project to either the ventral tegmentum or dorsal raphe.
Electrophysiological studies will determine whether dopamine or serotonin modulate MA activation of LHb
neurons and determine whether MA activation of TAAR1 in presynaptic terminals of ventral tegmental area
dopamine neurons or dorsal raphe serotonin neurons regulate the effects of MA using slices from mice with
and without functional TAAR1. Thus, this proposal utilizes genetic tools, circuit analysis via electrophysiology
and behavioral analysis to identify how MA engages LHb neurons in a TAAR1-dependent manner, whether
LHb circuits are necessary for MA-induced aversion behaviors, and whether they inhibit MA intake. This
strategy could be used to study effects of MA on TAAR1 signaling in other regions. The study of mechanisms
underl...

## Key facts

- **NIH application ID:** 10931577
- **Project number:** 5R01DA057420-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Susan L Ingram
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $545,655
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931577

## Citation

> US National Institutes of Health, RePORTER application 10931577, Role of lateral habenula in methamphetamine TAAR1-mediated synaptic plasticity and aversion (5R01DA057420-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10931577. Licensed CC0.

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