Neurotoxic biomarkers of ethanol exposure: from adolescent vulnerability to adult voluntary intake in rats of both sexes.

BACKGROUND

Ethanol use is frequently initiated during adolescence, a vulnerable developmental period with a great deal of neuro-remodeling, specially affecting hippocampal integrity, and with a unique sensitivity to drug abuse. Previous data evaluated the neurochemical effects exerted by either ethanol or cocaine alone in the adolescent brain, but few studies measured the combined negative impact of both drugs immediate during adolescence and later following withdrawal and drug re-exposure in adulthood and therefore will be the aim of this study.

METHODS

Male and female Sprague-Dawley rats were treated in adolescence with non-contingent paradigms of ethanol, cocaine, their combination, or vehicle. Hippocampal samples were collected in adolescence, during forced withdrawal and following voluntary exposure to ethanol in adulthood to evaluate signs of neurotoxicity by western blot (Fas-Associated protein with Death Domain [FADD], and the ratio between Neurofilament light chain protein, NF-L, and Brain-Derived Neurotrophic Factor, BDNF) or neurogenesis by immunohistochemistry (Ki-67, NeuroD).

RESULTS

Adolescent ethanol induced hippocampal neurotoxicity by decreasing FADD and increasing NF-L/BDNF ratio, paired with decreased neuronal differentiation as labeled by NeuroD. These effects reverted to normal in adulthood during withdrawal. NeuroD was decreased after adult voluntary ethanol consumption, but exclusively in rats previously exposed to adolescent ethanol. Adolescent cocaine alone did not induce any changes at any time-points examined. The neurochemical effects were observed independently of sex. Interestingly, NeuroD emerged as a biomarker of ethanol toxicity both in adolescence and adulthood.

CONCLUSIONS

Ethanol is a neurotoxic agent, and its toxicity is exacerbated by an early initiation during adolescence. Our conclusions reinforce the recommendation of avoiding and/or delaying the age of initial ethanol exposure, since it poses a prior vulnerability to its later impact in life.