# Gene-environment interaction: the brain CRF system in alcohol preferring msP rats

> **NIH NIH R37** · SCRIPPS RESEARCH INSTITUTE, THE · 2023 · $351,414

## Abstract

Program Director/Principal Investigator (Last, First, Middle):
Alcoholism is a chronically relapsing disorder that develops over time and is characterized by the transition
from recreational alcohol use to abuse and dependence. Negative emotional states, such as posttraumatic
stress disorder (PTSD) or anxiety, influenced by genetic factors or determined by environmental conditions
contribute to shaping this transition. On the other hand, chronic exposure to alcohol is a major determinant
for the occurrence of mood disorders (e.g., anxiety, depression, PTSD) and negative emotional states (i.e.,
dysphoria, irritability). The amygdalar nuclei [both the central nucleus of the amygdala (CeA) and
basolateral amygdala (BLA)] are considered a hub for negative emotional circuitry, and the role of the stress
peptide corticotropin-releasing factor (CRF) in this brain structure is critical for both development of alcohol
dependence and mood disorders/negative affect. During the previous funding period we provided essential
new insight into the relationship between innate overexpression of the CRF1 receptor system, stress
hypersensitivity and excessive ethanol consumption in genetically selected Marchigian Sardinian (msP)
rats. Our most recent results show that enhanced CRF signaling in msP rats is responsible for increased
hydrolytic activity of fatty acid amide hydrolase (FAAH) and blunted endocannabinoid (eCB) signaling in the
CeA/BLA, leading to enhanced GABA and glutamate transmission in the amygdala. Our hypothesis is that
such alterations contribute to enhance stress sensitivity and to exacerbate anxiety-like symptoms in the
msP rats, which may increase drinking to alleviate these negative conditions. Understanding the
mechanisms through with innate and environmental factors act/interact to dysregulate CRF/eCB
transmission in the BLA and CeA will provide new insight into the etiopathology of alcoholism, aiding the
development of new therapeutics for this still largely untreated medical condition. The research plan for this
competitive renewal is to investigate how alteration of eCB signaling in the amygdala triggered by innate (in
msP rats) or EtOH-induced (post-dependent Wistars) upregulation of the CRF1 system contributes to
excessive alcohol drinking and exacerbates maladaptive conditioned fear responses, similar to symptoms
of PTSD in humans. The ability to restore normal eCB function by FAAH inhibition, and therefore to
counteract excessive drinking and normalize fear responses, will be also studied. A better understanding of
the molecular mechanism underlying genotypic differences of the msP compared to outbred Wistar rats and
of neuroadaptations following exposure to alcohol, will provide novel insight into the innate susceptibility to
develop Alcohol Use Disorder and will be useful toward the development of new therapeutic agents to
alleviate alcohol dependence.
RELEVANCE (See instructions): The Marchigian Sardinian alcohol-preferring (msP) rat...

## Key facts

- **NIH application ID:** 10691414
- **Project number:** 5R37AA017447-13
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** MARISA ROBERTO
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $351,414
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691414

## Citation

> US National Institutes of Health, RePORTER application 10691414, Gene-environment interaction: the brain CRF system in alcohol preferring msP rats (5R37AA017447-13). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691414. Licensed CC0.

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