# Pivotal role of thalamic hypocretin transmission during EtOH seeking and relapse

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $435,375

## Abstract

A central problem in the treatment of ethanol (EtOH) addiction is the prevalence of relapse to EtOH use even
after protracted intervals of forced or self-imposed abstinence. Advances have been made in elucidating the
neurocircuitry that mediates craving and EtOH seeking, which provides insights into the neurobiological basis
of relapse. Functional brain imaging in humans and studies that use c-fos expression as a marker of neural
activation in rodents implicate interconnected cortical and limbic brain regions in response to drug cue-, drug
priming-, and stress-induced reinstatement. Major components of this circuitry include the medial prefrontal
cortex (mPFC), basolateral amygdala (BLA), central nucleus of the amygdala (CeA), bed nucleus of the stria
terminalis (BNST), ventral tegmental area (VTA), nucleus accumbens (NAC), hippocampus, thalamus (THAL),
and dorsal striatum. The hypocretin (Hcrt) system regulates a wide range of physiological processes, including
feeding, energy metabolism, and arousal, and is recruited by drugs of abuse, including EtOH. Of interest for
the present proposal, recent studies have demonstrated a critical role of Hcrt in the modulation of stress and a
possible anxiolytic effect of Hcrt receptor (Hcrt-r) antagonism. Hcrt neurons, located only in the hypothalamus,
project to the major components of the neurocircuitry that mediates EtOH seeking and innervates densely the
paraventricular nucleus of the thalamus (PVT). Recent evidence suggests that the PVT participates in the
modulation of reward function in general and drug-directed behavior in particular. Furthermore, it has been
shown that PVT is an important contributor in the regulation of stress, a critical factor that can induce intense
craving and trigger relapse in abstinent individuals. Earlier findings demonstrated selective recruitment of the
LH/DMH/PFA-PVT during EtOH seeking, and preliminary data suggest that a history of EtOH dependence
dysregulates the Hcrt/Hcrt-r system. Thalamic impairments are a key feature of EtOH-related brain dysfunction
in alcoholics, remaining to be determined are the extent to which a history of EtOH dependence dysregulates
Hcrt and whether this dysfunction will predict maladaptive compulsive EtOH-seeking (relapse) that is
precipitated by stress vs. normal (food-seeking) behavior. This proposal will test the hypothesis that a history of
EtOH dependence dysregulates Hcrt and its interaction with the PVT, and that this dysfunction will predict
compulsive EtOH seeking (relapse) precipitated by stress. Furthermore, using local gene silencing, this
proposal will test the hypothesis that the permanent decrease in Hcrt production via a viral vector will prevent
Hcrt transmission dysregulation in the PVT during dependence and therefore prevent exacerbated response to
stress during EtOH abstinence. This project is likely to highlight a previously unrecognized mechanism in the
etiology of compulsive EtOH seeking during abstinence; ultimately...

## Key facts

- **NIH application ID:** 10200612
- **Project number:** 5R01AA026999-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Remi Martin-Fardon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $435,375
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10200612

## Citation

> US National Institutes of Health, RePORTER application 10200612, Pivotal role of thalamic hypocretin transmission during EtOH seeking and relapse (5R01AA026999-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10200612. Licensed CC0.

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