Early-life exposure to antibiotics: impact on mesocorticolimbic circuit and drug response in adult rats
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2022-11
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Universidad de Valparaíso
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Instituto de Neurociencia
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Gut microbiota with a stable, rich, and diverse composition is associated with adequate brain development. Colonization of the infant gut begins at birth when partum exposes the newborn to a set of bacteria, most of them coming from the mother’s gut. Colonization then continues due to environmental factors (i.e.: diet), which goes on to provide microbial richness and diversity. Decreased richness and diversity of its composition has been related to several pathologies, including neuropsychiatric disorders such as drug addiction. Previous work from Dr. Bravo’s Lab demonstrates that early-life exposure to antibiotics (ELEA), trough oral administration of a non- absorbable broad-spectrum antibiotic cocktail to a pregnant Sprague-Dawley dam from embryonic day 18 to postnatal day 7, results in decreased gut microbial diversity and richness, while at the same time affecting dopamine receptor expression in Nucleus Accumbens, striatum, and ventral tegmental area (VTA), of the male offspring at 35 days of age, suggesting changes in pharmacology effects of drugs of abuse. Thus, this project aimed to evaluate ELEA effect within the dopaminergic circuitry and drug response in male and female adult rats (60 days of age on average). We observed that ELEA altered protein levels (tyrosine hydroxylase, and dopamine [DA] receptors 1 and 2) within the mesocorticolimbic system of naïve (no drug exposure whatsoever) adult rats, mainly on female animals, and we also found sexual differences that has never been reported. Also, after a 5-day conditioning protocol using 5 mg/Kg methylphenidate (MPH) as a dopamine transporter blocker, ELEA males showed an increased drug-seeking behavior, while ELEA females had an apparent ceiling effect of the conduct, along with a 3,4-dihydroxyphenylic acid content of VTA decrease, when compared to control females. On the other hand, acute MPH administration increased locomotor activity of ELEA females in a significant higher manner that what we observed on ELEA males. Additionally, ELEA decreased dorsolateral striatal in-vivo DA release only on females, which also showed a higher DA signal decay (Tau). To our knowledge, altogether these results show for the first time that ELEA alters the dopaminergic circuitry, conduct, and drug response of adult rats in a sex-dependent manner.
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ANTIBIOTICOS, DESARROLLO EMBRIONARIO, DOPAMINA, ACTIVIDAD MOTORA, Metilfenidato