# The role of 5HT2C receptor in RMTg response to cocaine

> **NIH NIH F30** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2020 · $50,520

## Abstract

Project Summary/Abstract
 The neurobiology of cocaine’s rewarding effects has been extensively characterized, but relatively little
is known about the pathways and processes that underlie cocaine’s aversive effects. Aversive responses to
cocaine are significant because they may modulate both the initial acquisition of drug-seeking, and later
behaviors such as relapse in experienced animals, and may underlie individual differences in susceptibility to
cocaine addiction. Prior work from our lab and others showed that activation of the rostromedial tegmental
nucleus (RMTg) by cocaine critically drives conditioned avoidance responses to cocaine, and that some of this
cocaine-induced RMTg activation is due to glutamatergic inputs from the lateral habenula (LHb). However, the
LHb only explains a portion of this effect, and roughly half of the activation is not dependent on the LHb, and
arises from unknown mechanisms.
 Using RNAseq I made the unexpected discovery that the RMTg expresses robust and enriched levels
of mRNA for the serotonin 2C receptor (gene name htr2c) relative to surrounding regions such as the VTA, and
that microinfusion of a specific 5-HT2CR antagonist into the RMTg significantly attenuated cocaine conditioned
avoidance. Because cocaine binds to both serotonin and dopamine uptake transporters, I postulated 5-HT2CR
activation at the RMTg might be a novel mechanism by which RMTg activates in response to cocaine and
contributes to cocaine’s aversive effects.
 In this proposal, I will definitively test the hypothesis that 5-HT2CR activation facilitates RMTg excitation,
and that the 5-HT2CR is necessary for RMTg response to cocaine and cocaine conditioned avoidance and
relapse. In specific aim 1, to determine the effect of 5-HT2C receptor activation on VTA-projecting RMTg
neurons, I will use in vitro slice electrophysiology techniques. In specific aim 2, to determine the role of 5-
HT2CR in driving RMTg and behavioral responses to cocaine, I will use AAV mediated shRNA to knock down 5-
HT2CR expression at the RMTg in vivo while measuring cocaine-induced RMTg activation and behavioral
responses. If successful, these studies will provide the first insight into the role of serotonin receptors in the
modulation of RMTg activity, identify a novel role of 5-HT2C receptor at the RMTg that acts in concert with LHb
inputs to mediate cocaine’s aversive effects, and identify 5-HT2CR antagonism to be a novel and valid strategy
for treating cocaine’s aversive effects and addiction.

## Key facts

- **NIH application ID:** 9916625
- **Project number:** 5F30DA048597-02
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Ying Chao
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9916625

## Citation

> US National Institutes of Health, RePORTER application 9916625, The role of 5HT2C receptor in RMTg response to cocaine (5F30DA048597-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9916625. Licensed CC0.

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