Rapamycin Improves Recognition Memory and Normalizes Amino-Acids and Amines Levels in the Hippocampal Dentate Gyrus in Adult Rats Exposed to Ethanol during the Neonatal Period

Abstract

The mammalian target of rapamycin (mTOR), a serine/ threonine kinase, is implicated in synaptic plasticity by controlling protein synthesis. Research suggests that ethanol exposure during pregnancy alters the mTOR signaling pathway in the fetal hippocampus. Thus, we investigated the influence of pre-treatment with rapamycin, an mTORC1 inhibitor, on the development of recognition memory deficits in adult rats that were neonatally exposed to ethanol. In the study, male and female rat pups received ethanol (5 g/kg/day) by intragastric intubation at postanatal day (PND 4-9), an equivalent to the third trimester of human pregnancy. Rapamycin (3 and 10 mg/kg) was given intraperitoneally before every ethanol administration. Short- and long-term recognition memory was assessed in the novel object recognition (NOR) task in adult (PND 59/60) rats. Locomotor activity and anxiety-like behavior were also evaluated to exclude the influence of such behavior on the outcome of the memory task. Moreover, the effects of rapamycin pre-treatment during neonatal ethanol exposure on the content of amino-acids and amines essential for the proper development of cognitive function in the dentate gyrus (DG) of the hippocampus was evaluated using proton magnetic resonance spectroscopy (1H MRS) in male adult (PND 60) rats. Our results show the deleterious effect of ethanol given to neonatal rats on long-term recognition memory in adults. The effect was more pronounced in male rather than female rats. Rapamycin reversed this ethanol-induced memory impairment and normalized the levels of amino acids and amines in the DG. This suggests the involvement of mTORC1 in the deleterious effect of ethanol on the developing brain.

Rapamycin Improves Spatial Learning Deficits, Vulnerability to Alcohol Addiction and Altered Expression of the GluN2B Subunit of the NMDA Receptor in Adult Rats Exposed to Ethanol during the Neonatal Period

“…Although we did not evaluate the influence of ethanol on the mTOR signaling pathway, pretreatment with rapamycin before ethanol administration in neonatal rats mitigated the negative effects of neonatal ethanol exposure on rat behavior and neurochemical evaluation. These data support the previous finding that gestational binge alcohol exposure dysregulates the fetal hippocampal mTOR system, has an impact on mTORC1 signaling, which plays essential roles in brain development and alters the proteins that complex with hippocampal mTOR, the functions of which have also been implicated in brain developmental processes [33,82]. Furthermore, it has been previously indicated that inhibition of GluN2B in the orbitofrontal cortex attenuates alcoholdependent mTORC1 activation, alcohol seeking and habitual responding for alcohol.…”

“…In the experiments, ethanol (95% w / v , Polmos, Poznan, Poland) was diluted with milk (Bebilon 1 Pronutra Plus, Nutricia, Warsaw, Poland) and administered intragastrically (i.g. ), at the dose of 5.0 (22.66%, v / v ) g/kg during PND4–9 according to the method described previously [ 33 ]. Rapamycin (Selleckchem, Munich, Germany) was dissolved in 0.9% NaCl and given intraperitoneally (i.p.…”

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

“…However, increase in locomotor activity is restricted to adolescence because it was not observed in the adult (PND61) rats in our study (Table 1). This finding supports previous evidence [32][33][34] that hyperactivity is characteristic mostly for children with FASD [35] and becomes subtler when they become older.…”

“…Published data show that emotionality (fear and/or anxiety) can [31] or cannot affect avoidance behavior [20]. However, our previous study indicated that neonatal ethanol-treated rats did not indicate anxiety-like behavior [32,33], therefore this factor could not have had influenced on the obtained results in the PA task.…”

L-Proline Activates Mammalian Target of Rapamycin Complex 1 and Modulates Redox Environment in Porcine Trophectoderm Cells

“…Amino acids and amino acid receptors have been shown to activate the mTOR signaling pathway. Activation of mTOR by nutrients, growth factors, energy status, and stress regulates cellular processes including growth, differentiation, and metabolism [ 49 , 50 ]. Further research revealed that proline enhanced the protein abundance of p-mTORC1 ( Figure 2 A), p-p70S6K ( Figure 2 B), p-S6 ( Figure 2 C), and p-4EB-BP1 ( Figure 2 D) at 0.5 mmol/L.…”