# Neurocircuitry Component - Zorrilla

> **NIH NIH P60** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $222,121

## Abstract

ABSTRACT
Alcohol use disorder (AUD) is a chronic relapsing disorder marked by lasting vulnerability to relapse due to
persistent experience of negative emotional protracted abstinence symptoms and related impairments in
inhibitory control over alcohol use behavior. Neurobiological understanding of and novel treatments that target
these protracted abstinence sequalae are needed to impact AUD relapse. Data from our ARC suggest a novel
hypothesis that relapse risk is increased by chronic ethanol-induced imbalance between cortical stress and anti-
stress systems in the infralimbic cortex (IL) that impair “top-down” control over the central nucleus of the
amygdala (CeA), leading to negative affective dysregulation and compulsive-like, recurrent alcohol use. The
Zorrilla Neurocircuitry component, in collaboration with our ARC colleagues, tests this hypothesis in 3 aims.
Aim 1 uses retro-DREADD manipulation to test the hypotheses that activity of the IL-CeA projection
bidirectionally modifies stress-induced relapse to alcohol-seeking, drinking in risky contexts and in response to
frustrative reward omission, and irritability-like behavior. Aim 2 will use systemic and intra-IL brain-site specific
administration of translatable small molecule nociceptin opioid peptide (NOP) receptor ligands and a short-acting
kappa opioid receptor (KOR) antagonist to test their effects on the increased stress-induced relapse, drinking
and irritability of post-dependent CIE rats. Aim 3 uses targeted and unbiased retrograde CAV2-Cre circuit-
defined proteomic analysis in STOPflox-MetRS* mice to identify altered expression and post-translational
modification of proteins in CeA-projecting IL neurons, by labeling nascent proteins produced during abstinence
with the methionine surrogate azido-nor-leucine (ANL). The collaborative studies with each ARC research
Component and Core seek to determine the causal role of the IL-CeA projection in stress relapse, drinking and
affective dysregulation during protracted abstinence. They also aim to provide translatable insight into the
systemic and IL role of KOR and NOP receptor systems with mechanistic neurophysiologic and whole-brain
network insight. Finally, they may refine or discover new molecular targets in this key stress-related cortico-
amygdalar projection linked to compulsive drinking and AUD relapse under stress and distress.

## Key facts

- **NIH application ID:** 10526269
- **Project number:** 2P60AA006420-40
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** ERIC P ZORRILLA
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $222,121
- **Award type:** 2
- **Project period:** 1983-12-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526269

## Citation

> US National Institutes of Health, RePORTER application 10526269, Neurocircuitry Component - Zorrilla (2P60AA006420-40). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10526269. Licensed CC0.

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