Alcohol-driven AMPA receptor dysregulation across the lifespan.

Alcohol use produces persistent alterations in glutamatergic signaling that evolve across the lifespan, with α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) emerging as major contributors to these neuroadaptations. Alcohol disrupts glutamate homeostasis and modifies AMPAR subunit composition as well as receptor trafficking, producing circuit-specific changes in synaptic plasticity within reward pathways. These AMPAR‑related adaptations increase excitatory drive strengthening behaviors that promote escalated alcohol use. Adolescence represents a particularly vulnerable period, as alcohol exposure during this developmental window interferes with the maturation of prefrontal and hippocampal circuits and induces long‑lasting alterations in excitatory signaling. In adulthood, repeated alcohol consumption produces AMPAR‑dependent changes that amplify the reinforcing properties of alcohol and contribute to maladaptive motivational states characteristic of alcohol use disorder (AUD). Disruption of AMPAR regulatory mechanisms by alcohol may overlap mechanistically with age‑related synaptic weakening and early neurodegenerative processes, particularly those associated with cognitive impairment. Together, these findings highlight AMPAR-centered mechanisms as a potential link between alcohol use disorder, age-related cognitive decline, and neurodegeneration.