UC San Diego

Alcohol use disorder (AUD) is a psychological disorder affecting millions worldwide, and current medications have limited efficacy. AUD studies in male rats have shown hippocampal neurobiological changes, such as proliferation of neural progenitor cells (NPCs) during withdrawal; however, the link between this phenomenon to increased risks of ethanol-seeking behavior is unclear. Furthermore, studies must be conducted in female rats to highlight sex differences in the neurobiology linked to AUD. Additionally, studies show that alcohol promotes neuroinflammation and disrupts blood-brain-barrier (BBB) integrity. In this study, we used a pharmacogenetic rat model (GFAP-TK rats), a CIE model of moderate to severe AUD (CIE), and fed Valcyte to inhibit NPC proliferation in understudied female rats to investigate neurobiological associations to AUD. CIE produced robust relapse to drinking behavior and reinstatement of ethanol seeking, and Valcyte diminished this effect. Hippocampal quantitative immunohistochemistry showed that Valcyte reduced Ki-67 cells compared to vehicle group, indicating ablation of NPC proliferation. 3-D structure analysis of Iba-1 microglia cells showed that CIE increased microglial activity in the hippocampus. Valcyte prevented this effect, suggesting suppression of neuroinflammatory response by inducing microglial inhibition. Reduced seeking by Valcyte was associated with normalization of plasma cytokines and chemokines, suggesting a role for NPCs in peripheral inflammation. Western blot analysis showed that CIE reduced Claudin-5 expression, and Valcyte rescued these protein levels, indicating increased BBB integrity. Altogether, blocking NPCs suppressed neuroinflammation factors, promoted BBB integrity, and decreased motivation to seek ethanol. These findings suggest a promising route to develop a new therapy for AUD.