Preclinical Models of Alcohol Use and Alcohol-Induced Neurotoxicity: Behavioral, Cognitive, and Developmental Perspectives

OBJECTIVE: This review conceptualizes ethanol and methanol neurotoxicity through a tri-domain framework encompassing motivational, degenerative, and developmental mechanisms, and integrates decades of rodent research into a multidimensional map of how alcohol reshapes the brain. It emphasizes exposure route-specific paradigm, oral gavage, vapor inhalation, and intraperitoneal administration, as translational anchors linking behavioral, metabolic, and molecular signatures. METHOD: A literature search was conducted across PubMed, Scopus, and Web of Science databases for articles published between June 1999 and May 2026. Search terms integrated keywords related to alcohol exposure routes and neurotoxicity (e.g., ethanol, methanol, neurodegeneration, prenatal/adolescent exposure, oral gavage, vapor, and injection paradigms). Boolean operators and manual citation tracking were utilized. Out of 205 initially identified articles, 182 studies meeting selection criteria were included in the final synthesis. RESULTS: Chronic gavage models effectively capture nutrient-metabolic interactions under sustained drinking, vapor inhalation isolates central oxidative and inflammatory cascades under stress-neutral conditions, and injection paradigms offer mechanistic precision for acute mitochondrial dysfunction. Hybrid protocols reveal time-coded dynamics of degeneration and recovery. Developmental studies demonstrate that prenatal and adolescent alcohol exposure drives epigenetic remodeling, DNA methylation drift, histone acetylation, and microRNA dysregulation, leading to long-term deficits in cortical maturation and cognitive control. Methanol models extend this neuroenergetic spectrum through formate-driven mitochondrial failure and optic-cerebellar injury. CONCLUSIONS: The tri-domain framework integrates diverse rodent paradigms across exposure routes and life stages. To enhance clinical translation, future research should leverage multi-omics, connectomic mapping, and bioengineered platforms (e.g., organoids and brain-on-chip) to identify early molecular markers and targeted neuroprotective interventions.