Donepezil Reverses Alcohol‐Induced Changes in Hippocampal Neurogenic and Glial Responses Following Adolescent Intermittent Ethanol Exposure Into Adulthood in Female Rats

Adolescent intermittent ethanol (AIE) exposure leads to persisting increases in glial markers and significantly decreases the neurogenic niche in the dentate gyrus of the hippocampus. Our previous study indicated that donepezil (DZ), a cholinesterase inhibitor, can reverse the AIE effect of decreased doublecortin (DCX), a neurogenic marker, and increased cleaved caspase 3, a marker of apoptosis, in the dentate gyrus of male rats. However, to date, no studies have assessed the effects of DZ on AIE effects in females. The purpose of this study was to determine whether DZ can reverse neuroimmune, neurogenic, and neuronal death effects in adulthood after AIE in female rats. Adolescent female rats were given 14 doses of ethanol (5 g/kg) over 24 days by intragastric gavage. Seventeen days later, DZ (2.5 mg/kg, 1.88 mL/kg, i.g., in water) was then administered daily for 4 days prior to sacrifice. Immunohistochemical techniques were utilized to determine the effects of DZ on AIE-induced changes in neurogenesis, cell death, glial, and neuroimmune markers. As expected, AIE decreased the neurogenic markers DCX, SOX2, and Ki-67 in the dentate gyrus and also caused an increase in the glial markers GFAP and Iba-1 in the hippocampus. The effects of AIE on neurogenic and glial markers were reversed by DZ treatment, but the reversal of AIE effects on glial markers was regionally specific within the hippocampus. Overall, these findings indicate that systemic DZ in adult female rats ameliorates the effects of AIE on neurogenesis, neuronal cell death, neuroimmune markers, and glial activation markers. Future studies will determine if DZ alters hippocampally driven behaviors, as well as the mechanisms underlying donepezil's effects.