In utero exposure to dexamethasone causes a persistent and age-dependent exacerbation of the neurotoxic effects and glia activation induced by MDMA in dopaminergic brain regions of C57BL/6J mice.

Abstract

Clinical and preclinical evidence indicates that prenatal exposure to glucocorticoids may induce detrimental effects in the offspring, including reduction in fetal growth and alterations in the CNS. On this basis, the present study investigated whether in utero exposure to high levels of glucocorticoids is a risk factor that may lead to an exacerbation of the central noxious effects induced by psychoactive drugs consumed later in life. To this end, pregnant C57BL6/J dams were treated with dexamethasone (DEX, 0.05 mg/kg per day) from gestational day 14 until delivery. Thereafter, the male offspring were evaluated to ascertain the magnitude of dopaminergic damage, astrogliosis and microgliosis elicited in the nigrostriatal tract by the amphetamine-related drug 3,4--methylenedioxymethamphetamine (MDMA, 4 × 20 mg/kg, 2 h apart, sacrificed 48 h later) administered at either adolescence or adulthood. Immunohistochemistry was performed in the substantia nigra pars compacta (SNc) and striatum, to evaluate dopaminergic degeneration by measuring tyrosine hydroxylase (TH), as well as astrogliosis and microgliosis by measuring glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (IBA-1), respectively. Moreover, immunohistochemistry was used to ascertain the co-localization of IBA-1 with either the pro-inflammatory interleukin (IL) IL-1β or the anti-inflammatory IL IL-10, in order to determine the microglial phenotype. In utero administration of DEX induced dopaminergic damage by decreasing the density of TH-positive fibers in the striatum, although only in adult mice. MDMA administration induced dopaminergic damage and glia activation in the nigrostriatal tract of adolescent and adult mice. Mice exposed to DEX in utero and treated with MDMA later in life showed a more pronounced loss of dopaminergic neurons (adolescent mice) and astrogliosis (adolescent and adult mice) in the SNc, compared with control mice. These results suggest that prenatal exposure to glucocorticoids may induce an age-dependent and persistent increase in the susceptibility to central toxicity of amphetamine-related drugs used later in life.

• Authors: Giulia Costa, Stefan Spulber, Elena Paci, Maria Antonietta Casu, Sandra Ceccatelli, Nicola Simola, Micaela Morelli
• Journal: Neurotoxicology (Neurotoxicology) Vol. 83 Pg. 1-13 (03 2021) ISSN: 1872-9711 [Electronic] Netherlands
• PMID: 33338551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Aif1 protein, mouse
• Calcium-Binding Proteins
• Glial Fibrillary Acidic Protein
• Glucocorticoids
• IL10 protein, mouse
• IL1B protein, mouse
• Interleukin-1beta
• Microfilament Proteins
• glial fibrillary astrocytic protein, mouse
• Interleukin-10
• Dexamethasone
• Tyrosine 3-Monooxygenase
• N-Methyl-3,4-methylenedioxyamphetamine

Topics

• Age Factors
• Animals
• Brain (drug effects, metabolism, pathology)
• Calcium-Binding Proteins (metabolism)
• Dexamethasone (toxicity)
• Disease Models, Animal
• Disease Progression
• Dopaminergic Neurons (drug effects, metabolism, pathology)
• Female
• Gestational Age
• Glial Fibrillary Acidic Protein (metabolism)
• Gliosis
• Glucocorticoids (toxicity)
• Interleukin-10 (metabolism)
• Interleukin-1beta (metabolism)
• Male
• Maternal Exposure
• Mice, Inbred C57BL
• Microfilament Proteins (metabolism)
• N-Methyl-3,4-methylenedioxyamphetamine
• Nerve Degeneration
• Neuroglia (drug effects, metabolism, pathology)
• Neurotoxicity Syndromes (etiology, metabolism, pathology)
• Pregnancy
• Prenatal Exposure Delayed Effects
• Tyrosine 3-Monooxygenase (metabolism)
• Mice