Aversive Learning Deficits and Depressive-Like Behaviors Are Accompanied by an Increase in Oxidative Stress in a Rat Model of Fetal Alcohol Spectrum Disorders: The Protective Effect of Rapamycin

• Published in: International journal of molecular sciences Vol. 22; no. 13; p. 7083
• Main Authors: Lopatynska-Mazurek, Malgorzata, Komsta, Lukasz, Gibula-Tarlowska, Ewa, Kotlinska, Jolanta H.
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01-07-2021; MDPI
• Subjects: adult rats; Avoidance learning; Behavior; Brain research; depressive-like behavior; Ethanol; Experiments; Exposure; Fetal alcohol syndrome; Hippocampus; Homeostasis; Hypotheses; Inhibitors; Kinases; learning; Lipid peroxidation; Lipids; Memory; Mental task performance; neonatal ethanol exposure; Neonates; Neurodegeneration; Oxidative stress; Prefrontal cortex; Pregnancy; Prenatal experience; Rapamycin; Rodents; Signal transduction; Swimming behavior; Tacrolimus; TOR protein; Variance analysis
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22137083

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin—a selective inhibitor of mTORC1, Torin-2—a non-selective mTORC1/mTORC2 inhibitor, and FK-506—a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.