Kynurenine pathway as a possible link between ethanol exposure produced behavioral alterations and neuroinflammation

Leticia Gil de Biedma-Elduayen¹Pablo Gimenez Gomez²Nuria Morales-Puerto¹Rebeca Vidal Casado¹Alvaro del Río García¹Carlos Núñez de la Calle¹Lluna Careaga Heres¹Maria Dolores Gutiérrez López³Esther O’Shea^1*Maria Isabel Colado^1*

• ¹Departamento de Farmacología y Toxicología, Facultad de Medicina, Universidad Complutense, Madrid, Spain
• ²University of Massachusetts Chan Medical School,, Worcester, Massachusetts, United States
• ³Complutense University of Madrid, Madrid, Spain

Introduction. The neuroimmune actions of ethanol have recently gained significant attention.Concurrently, the kynurenine pathway, the main catabolic route of tryptophan (TRP), has emerged as a novel target for modulating drug abuse and as a critical immune regulator. This pathway is implicated in behavioral and cognitive alterations, including anxiety, depression, and memory impairmentconditions closely associated with ethanol (EtOH) dependence. The kynurenine pathway is activated under inflammatory and immune conditions.Objective. We previously demonstrated that chronic EtOH consumption increases kynurenine (KYN) levels in mice. Here, we investigate the effect of EtOH dependence and withdrawal on behavioral and cognitive parameters, the nucleus accumbens (NAc) transcriptome, and KYN, TRP and serotonin (5-HT) levels and KYN/TRP and 5-HT/TRP ratios in mice.Methods. Adult male mice were subjected the Chronic Intermittent Ethanol (CIE) paradigm, a model for dependence and withdrawal. Twenty-four hours post-EtOH exposure, we analyzed behavioral and cognitive parameters, sequenced the NAc transcriptome, and measured KYN, TRP and 5-HT levels as well as KYN/TRP and 5-HT/TRP ratios in plasma, limbic forebrain, cortex and cerebellum using HPLC.Results. The CIE model induced anxiety-like behavior and memory impairment. Transcriptomic analysis of the NAc revealed immune system activation, including upregulation of immune and inflammation-related genes. Furthermore, chronic EtOH exposure increased KYN levels and the KYN/TRP ratio across plasma and brain regions.This study suggests that chronic EtOH exposure induces neuroimmune activation, which may trigger KYN pathway activation and contribute to anxiety and memory deficits observed in the CIE model.