Abstract

Ethanol exposure increases oxidative stress in developing organs, including the brain. Antioxidant treatment during maternal ethanol ingestion improves behavioral deficits in rodent models of fetal alcohol spectrum disorder (FASD). However, the impact of general antioxidant treatment in their adult offspring and the Specific Reactive Species (ROS)-dependent mechanism, are not fully understood. We hypothesized that pre and early postnatal ethanol exposure (PEE) modifies redox homeostasis, in particular NOX2 function during reward signaling in the mesocorticolimbic pathway, which reinforces the effects of alcohol. We developed a FASD rat model which was evaluated during adolescence (P21) and adulthood (P70). We first studied whether redox homeostasis is affected in PEE animals, by analyzing mRNA expression of SOD1, CAT, and Gpx1. We found that PEE reduced the mRNA levels of these three anti-oxidant enzymes in PFC and HIPP at P21 and in the VTA at P70. We also analyzed basal mRNA and protein expression of NOX2 subunits such as gp91phox, p22 phox, and p47 phox, in mesocorticolimbic brain areas of PEE rat brains. At P21, gp91 phox, and p47 phox levels in the VTA were decreased. At P70, gp91 phox mRNA levels was decreased in HIPP and both mRNA and protein levels were decreased in PFC. Since NOX2 is regulated by the N-methyl-D-aspartate Receptor (NMDAR), we analyzed NMDAR mRNA expression and found differential expression of NMDAR subunits (NR1 and NR2B) in the PFC that was age dependent, with levels decreased at P21 and increased at P70. The analysis also revealed decreased NR2B mRNA expression in HIPP and VTA at P70. Offspring from maternal ethanol users consumed 25% more ethanol in a free choice alcohol consumption test than control rats, and showed place preference for an alcohol-paired compartment. In vivo inhibition of NOX2 using apocynin in drinking water, or infusion of blocked peptide gp91 phox ds in the VTA normalized alcohol place preference, suggesting that NOX2 plays an important role in addictive like behavior. Taken together, PEE significantly affects the expression of antioxidant enzymes, NOX2, NMDAR in an age, and brain region dependent manner. Moreover, we demonstrate that NOX2 regulates alcohol seeking behavior.

Highlights

  • Alcohol and tobacco are legal substances used by thousands of people worldwide daily

  • We found that several enzymes involved in redox homeostasis -CAT, SOD, Glutathione peroxidase isoform 1 (Gpx1), and NOX2- and N-methyl-D-aspartate Receptor (NMDAR) subunits were deregulated in postnatal ethanol exposure (PEE) rats

  • Our results suggest that altered redox homeostasis along with NOX2 dependent neuronal activity are associated with augmented alcohol seeking behavior in adult PEE male animals

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Summary

Introduction

Alcohol and tobacco are legal substances used by thousands of people worldwide daily. Abuse of these substances can lead to serious long lasting effects to human health, as well as high social and economic impacts. Moderate maternal drinking (1–2 drinks per day) does not typically cause full-blown FAS; it is associated with cognitive and behavioral alterations in the offspring, probably expressed during demanding situations (Streissguth et al, 1990, 1994; Willford et al, 2004). Since there is no existing information about offspring born under these conditions, the prevalence of neurobiological abnormalities of children prenatally exposed to alcohol is probably higher than that of individuals diagnosed with FASD

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