# Main Research Component 3: Developmental sensitivities to alcohol: opposing actions of cytokines on fear conditioning during intoxication and withdrawal

> **NIH NIH P50** · STATE UNIVERSITY OF NY,BINGHAMTON · 2022 · $298,578

## Abstract

PROJECT SUMMARY/ABSTRACT
MAIN RESEARCH COMPONENT 3
Alcohol use and abuse represents a substantial threat to public health. Age of first alcohol exposure is a critical
determinant of developmental trajectory and subsequent health status later in life, with prenatal and adolescent
periods emerging as developmental epochs during which alcohol exposure is particularly prevalent.
Neuroimmune consequences of alcohol have emerged as novel mechanisms that may contribute to changes
in alcohol reinforcement, dependence, and ultimately the development of alcohol-related brain damage.
Importantly, exposure to acute, binge-like doses of ethanol (EtOH) in rodents produce time-dependent
changes in cytokine expression in which Interleukin-6 (IL-6) is substantially elevated in key limbic structures
(amygdala, PVN and hippocampus) during acute EtOH intoxication. In contrast, expression of both IL-1β and
TNFα tends to surge in these same structures during withdrawal from acute EtOH exposure. Surprisingly,
adolescent rats (P31-33) displayed severely reduced cytokine responses to acute EtOH intoxication. These
findings suggest that adolescent rats may have a functionally immature neuroimmune response relative to
young adults. Paradoxically, however, adolescent Chronic Intermittent EtOH (CIE) exposure sensitized the
intoxication-related IL-6 response evoked by a binge-like dose of EtOH later in life (P70 young adults). Thus,
adolescents appear to be less sensitive to acute EtOH-induced cytokine responses, while at the same time
being vulnerable to long-term sensitization of neuroimmune processes resulting from adolescent CIE
exposure. However, the functional significance of these acute, EtOH-induced cytokine changes observed
across the intoxication-withdrawal cycle remain obscure. This proposal will utilize contextual fear conditioning
procedures as an animal model of emotional learning, and to test the functional relevance of EtOH-dependent
expression of cytokines. Consistent findings demonstrate that EtOH impairs fear conditioning when training
occurs within a short time-frame after EtOH exposure (i.e., during intoxication), whereas conditioning during
EtOH withdrawal tends to enhance fear conditioning. The studies proposed here will therefore examine the
phase-specific influence of EtOH on fear conditioning. Our central hypothesis is that phase-specific expression
of cytokines in the basolateral amygdala (BLA) produce opposing actions on BLA excitability and subsequent
fear conditioning. These studies will also examine long-term adaptations in neuroimmune function and
resultant consequences following adolescent CIE. In this way, the proposed studies will be among the first to
examine how phase-specific, EtOH-induced cytokine expression translates into age-specific, cognitive and
behavioral outcomes of early EtOH exposure.

## Key facts

- **NIH application ID:** 10470010
- **Project number:** 5P50AA017823-14
- **Recipient organization:** STATE UNIVERSITY OF NY,BINGHAMTON
- **Principal Investigator:** Terrence Deak
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $298,578
- **Award type:** 5
- **Project period:** 2009-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10470010

## Citation

> US National Institutes of Health, RePORTER application 10470010, Main Research Component 3: Developmental sensitivities to alcohol: opposing actions of cytokines on fear conditioning during intoxication and withdrawal (5P50AA017823-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10470010. Licensed CC0.

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