Effects of omega-3 fatty acids on CB1 cannabinoid receptor localization in the hippocampal CA1 region following alcohol withdrawal in adolescent male mice

Adolescent binge drinking has detrimental effects on brain function, leading to long-lasting impairments in synaptic plasticity, cognition, and behavior. These effects are mediated, in part, by disruption of the endocannabinoid system (ECS) and its cannabinoid type-1 (CB1) receptor. Alcohol consumption also depletes omega-3 fatty acids, which are essential for maintaining cell membrane integrity and supporting brain function. This depletion impairs synaptic plasticity by disrupting endocannabinoid signaling and reducing CB1 receptor expression and function. Conversely, enhancement of the ECS can restore brain function and reverse the loss of endocannabinoid-dependent synaptic plasticity associated with omega-3 deficiency. Notably, omega-3 supplementation has been shown to restore CB1 receptor expression in specific brain regions in adult mice following adolescent alcohol exposure. However, despite the established interplay between alcohol, omega-3, and the ECS, the direct impact of omega-3 supplementation on the subcellular localization of CB1 receptors after alcohol exposure remains poorly understood. In this study, we used immunoelectron microscopy to investigate whether omega-3 supplementation influences CB1 receptor distribution in the hippocampal CA1 region following alcohol withdrawal in adolescent male mice. Our results demonstrate that omega-3 partially restore the excitatory/inhibitory balance disrupted by alcohol, as evidenced by an increased number of excitatory terminals and a significant reduction in inhibitory terminals. However, the distribution and density of CB1 receptors within neuronal and glial compartments remain unchanged following alcohol exposure and omega-3 supplementation. These findings highlight novel structural effects of omega-3 in mitigating alcohol-induced brain damage.