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Improving behavioral deficits induced by perinatal ethanol and stress exposure in adolescent male rat progeny via maternal melatonin treatment

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Abstract

Background and aim

Early-life stressful situations and binge drinking have been thus far acknowledged as two burdensome conditions that potentially give rise to negative outcomes and then synergistically affect brain development. In this context, the hippocampus, with the greatest number of glucocorticoid receptors (GCRs) in the brain, is responsible for regulating negative responses to stress. Prolonged glucocorticoid (GC) exposure can accordingly cause oxidative stress (OS), leading to cognitive and emotional dysfunction. Against this background, melatonin, as a powerful antioxidant and hypothalamus–pituitary–adrenal (HPA) axis regulator, was administered in this study to ameliorate cognitive impairments induced by perinatal ethanol and stress exposure in adolescent male rat progeny.

Methods

Wistar rat dams were exposed to ethanol (4 g/kg) and melatonin (10 mg/kg) from gestational day (GD) 6 to postnatal day (PND) 14 and then limited nesting material (LNS) from PND0 to PND14 individually or in combination. Maternal behavior was then investigated in mothers. Afterward, the plasma corticosterone (CORT) concentration, the OS marker, the corticotropin-releasing hormone receptor type 1 (CRHR1) expression, and the GCR and brain-derived neurotrophic factor (BDNF) levels were measured in the male pups. Moreover, behavioral tasks, including the elevated plus maze (EPM), the Morris water maze (MWM), the novel object recognition (NORT), and the object-location memory (OLM) tests were completed and assessed.

Results

The quantity and quality of maternal care significantly decreased in the mothers with dual exposure to ethanol and stress. The plasma CORT concentration in the progeny also dropped in the Ethanol + LNS group, but the risk-taking behavior elevated significantly. The ethanol and stress exposure further revealed a significant fall in the GCR and CRHR1 expression levels, compared with stress alone. The results of learning and memory tasks also indicated a significant reduction in spatial learning and memory among animals exposed to ethanol and stress. The BDNF mRNA levels correspondingly increased in the Ethanol + LNS group, compared with LNS alone. In the presence of ethanol and stress, the superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities correspondingly declined. On the other hand, the malondialdehyde (MDA) levels augmented in the hippocampus of the animals with ethanol and LNS dual exposure, as compared with the control group. Melatonin treatment (MT) thus improved nursing behaviors in dams, prevented OS, enhanced the CRHR1 and GCR expression, and reduced the BDNF levels to the similar ones in the control group. The animals in the Ethanol + LNS + MT group ultimately showed an ameliorated performance at behavioral tasks, including the memory and risk-taking behavior.

Conclusion

It was concluded that MT could prevent stress response and memory impairments arising from dual exposure to ethanol and stress by inhibiting OS.

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Data Availability

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

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Acknowledgements

We acknowledge Damghan University for supporting this work.

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Authors and Affiliations

  1. School of Biology, Damghan University, Damghan, Iran

    Farzaneh Bagheri, Iran Goudarzi, Taghi Lashkarbolouki & Mahmoud Elahdadi Salmani

  2. Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Afsaneh Goudarzi

  3. Univ. Lille, CNRS, UMR 8576 - UGSF - Unité de Glycobiologie Structurale Et Fonctionnelle, 59000, Lille, France

    Sara Morley-Fletcher

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Contributions

F.B. carried out all the experiments and wrote the manuscript; I.G. designed the study’s research project, wrote the manuscript, and helped with data interpreting; T.L. and A.F. assisted with the molecular study, contributed with data interpretation, and assisted in manuscript editing; M.E.S. contributed to data interpretation, and S.M.F. contributed in study design and manuscript editing. The final manuscript was read and approved by all writers.

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Correspondence to Iran Goudarzi.

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Highlights

1. Postnatal melatonin treatment (MT) improved maternal behavior in dams throughout perinatal ethanol and stress dual exposure.

2. Maternal melatonin administration increased risk-taking behaviors in male rat progeny by modulating their responses to stress.

3. Melatonin prevented learning and memory impairments induced by perinatal ethanol and stress exposure in rat progeny due to its antioxidant capacity.

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Bagheri, F., Goudarzi, I., Lashkarbolouki, T. et al. Improving behavioral deficits induced by perinatal ethanol and stress exposure in adolescent male rat progeny via maternal melatonin treatment. Psychopharmacology 241, 153–169 (2024). https://doi.org/10.1007/s00213-023-06470-z

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