# Paraventricular thalamic control of opioid withdrawal and relapse

> **NIH NIH K99** · UNIVERSITY OF COLORADO DENVER · 2020 · $132,626

## Abstract

Project Summary/Abstract
Clinical studies indicate that the aversive somatic states experienced during opioid withdrawal predict drug
craving and increase the risk of relapse. However, little is known about the neural circuitry mediating these
aversive states, or how that circuitry interacts with known components of the neural circuitry mediating relapse
to opioid seeking. Recently, the paraventricular thalamic (PVT) projection to the nucleus accumbens (NAc) was
implicated in opioid withdrawal symptoms in mice exposed to repeated non-contingent morphine. However, it is
unknown whether withdrawal from heroin self-administration engages the PVT➝NAc pathway to drive relapse
by precipitating an aversive and/or painful state. To fill this gap in knowledge, during the K99 mentored phase of
this proposal, I will receive training in optogenetics and brain slice electrophysiology to manipulate neural circuits
implicated in heroin withdrawal and relapse. I will use optogenetics and chemogenetics to determine whether
this pathway is necessary and sufficient to drive aversion or hyperalgesia during heroin withdrawal, as well as
relapse to heroin seeking. I will validate the functionality of the optogenetic and chemogenetic approaches in
vitro using brain slice electrophysiology. My preliminary data indicate that activating the PVT➝NAc pathway is
sufficient to drive aversion and heroin seeking during acute and extended withdrawal after abstinence from
heroin self-administration, but not after extinction training. The PL➝NAc pathway has been proposed as a “final
common pathway” to drug seeking and it has been shown to drive heroin seeking after extinction training. The
extinction procedure may thus engage the prefrontal cortex to diminish the role of the PVT➝NAc pathway in
heroin seeking. A central hypothesis of this proposal is that the prelimbic cortex (PL) drives heroin seeking during
acute opioid withdrawal and after abstinence through an indirect PL➝PVT➝NAc pathway, but through a direct
PL➝NAc pathway after extinction training. During the R00 independent phase of this proposal I will test this
hypothesis using chemogenetics to inhibit the PL➝PVT pathway to attenuate heroin withdrawal-induced
hyperalgesia and relapse. One means by which this shift in circuits may occur, depending on withdrawal
modality, is by shifting glutamatergic drive to the same population of NAc neurons that drive heroin seeking. To
assess this, I will investigate whether a subset of NAc neurons receives convergent inputs from both the PL and
PVT using slice electrophysiology. Another means by which this circuitry may evolve to drive heroin seeking is
through changes in synaptic strength within PL➝PVT➝NAc pathway. I will thus investigate synaptic strength
(measured as AMPA/NMDA ratio) within this circuit. Next, I will test the ability of a long-term depression protocol
(LTD) in vitro to normalize identified changes in synaptic strength, and then apply the same protocol in vivo to
redu...

## Key facts

- **NIH application ID:** 10055326
- **Project number:** 1K99DA048974-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Giuseppe Giannotti
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $132,626
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055326

## Citation

> US National Institutes of Health, RePORTER application 10055326, Paraventricular thalamic control of opioid withdrawal and relapse (1K99DA048974-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10055326. Licensed CC0.

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