Abstract
Ethanol exposure during pregnancy alters the mammalian target of rapamycin (mTOR) signaling pathway in the fetal brain. Hence, in adult rats exposed to ethanol during the neonatal period, we investigated the influence of rapamycin, an mTOR Complex 1 (mTORC1) inhibitor, on deficits in spatial memory and reversal learning in the Barnes maze task, as well as the ethanol-induced rewarding effects (1.0 or 1.5 g/kg) using the conditioning place preference (CPP) paradigm. Rapamycin (3 and 10 mg/kg) was given before intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4–9 (an equivalent to the third trimester of human pregnancy). Spatial memory/reversal learning and rewarding ethanol effect were evaluated in adult (PND60–70) rats. Additionally, the impact of rapamycin pre-treatment on the expression of the GluN2B subunit of NMDA receptor in the brain was assessed in adult rats. Our results show that neonatal ethanol exposure induced deficits in spatial memory and reversal learning in adulthood, but the reversal learning outcome may have been due to spatial learning impairments rather than cognitive flexibility impairments. Furthermore, in adulthood the ethanol treated rats were also more sensitive to the rewarding effect of ethanol than the control group. Rapamycin prevented the neonatal effect of ethanol and normalized the GluN2B down-regulation in the hippocampus and the prefrontal cortex, as well as normalized this subunit’s up-regulation in the striatum of adult rats. Our results suggest that rapamycin and related drugs may hold promise as a preventive therapy for fetal alcohol spectrum disorders.
Highlights
The primary aim of our research is to examine whether the mTOR Complex 1 (mTORC1) inhibitor, rapamycin, when used as pre-treatment before every ethanol administration during the neonatal period, can protect adult rats against the deleterious effect of ethanol on learning and memory
PND4-9 on the Acquisition Memory of the Barnes-Maze Task in Adult (PND61–65) Male and Acquisition of spatial memory in the training phase was evaluated by a decrease in the latency time and the number of errors to reach the escape box for five consecutive days (PND61–65)
In the number of primary errors committed by rats, a four-way analysis of variance (ANOVA) with repeated measures showed a significant effect of rapamycin pre-treatment (F(2,464) = 50.17; p < 0.001), ethanol administration (F(1,464) = 72.17; p < 0.001), testing day (F(4,464) = 309.1; p < 0.001) and significant contribution of sex factor (F(1,464) = 143.4 p < 0.001)
Summary
Alcohol consumption during pregnancy has profound effects on structure and function in the developing human brain. Fetal alcohol spectrum disorder (FASD) is a term used to describe the effects that can occur in an individual with prenatal alcohol exposure [1]. These effects can include cognitive, emotional and motor deficits, together with characteristic morphological abnormalities [2,3]. In addition to verbal working learning disabilities, children with FASD struggle with spatial memory deficits that are directly related to abnormalities in the development of the hippocampus [4].
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