# Neurocircuitry Component - George & Zorrilla

> **NIH NIH P60** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $417,960

## Abstract

Abstract
A key issue in the alcohol field is identification of the neuronal circuits responsible for the loss of control over
alcohol drinking in dependence. Loss of control has long been hypothesized to result from dysfunction of the
frontal lobes and subsequent disinhibition (or activation) of subcortical systems that underlie stress, anxiety,
reward, pain, and habits. Recent work has also causally implicated an ensemble in the central nucleus of the
amygdala as required for excessive drinking and anxiety-like behavior during abstinence. The goal of the
Neurocircuitry Component is to integrate these views by identifying the cortical pathways upstream (cortico-
amygdalar) and downstream (amygdalo-cortical) of the CeA that contribute to the compulsivity of alcohol-
drinking and negative emotional behavior. The first hypothesis in this proposal is that reduced infralimbic and
greater anterior insula glutamatergic outflow to the amygdala promotes more compulsive drinking, with greater
anxiety- and irritability-like behavior in abstinence. Reciprocally, the second hypothesis is that dysregulation of
the prefrontal cortex partially results from activation of a neuronal ensemble in the CeA that promotes
compulsive alcohol drinking and abstinence symptoms via recruitment of direct and indirect amygdalo-cortical
projections to the infralimbic cortex and anterior insula. The third hypothesis is that dysregulated activation in
cortico-amygdalo-cortical loops can be normalized by a selective glucocorticoid receptor antagonist or
microtubule-associated protein-type 2 (MAP-2) ligand. This project may have a sustained and powerful impact
on the field by (1) causally implicating specific cortico-amygdalo-cortico loops in the compulsivity of alcohol
drinking and emergence of negative emotional states during abstinence and 2) identifying a circuit mechanism
for the efficacy of glucocorticoid receptor antagonists and MAP-2 ligands to reduce drinking and negative
emotional symptoms.

## Key facts

- **NIH application ID:** 9836780
- **Project number:** 5P60AA006420-37
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Olivier George
- **Activity code:** P60 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $417,960
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836780

## Citation

> US National Institutes of Health, RePORTER application 9836780, Neurocircuitry Component - George & Zorrilla (5P60AA006420-37). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9836780. Licensed CC0.

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