Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

2017
Authors
Batinić, Bojan
Santrač, Anja

Jančić, Ivan

Li, Guanguan
Vidojević, Aleksandra
Marković, Bojan

Cook, James M.

Savić, Miroslav

Article (Published version)

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We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in am...niotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.
Keywords:
MP-III-022 / Neurochemistry / Pharmacokinetic profile / Cytokines / PreadolecenceSource:
International Journal of Developmental Neuroscience, 2017, 61, 31-39Publisher:
- Pergamon-Elsevier Science Ltd, Oxford
Funding / projects:
DOI: 10.1016/j.ijdevneu.2017.06.001
ISSN: 0736-5748
PubMed: 28610974
WoS: 000408288000004
Scopus: 2-s2.0-85020699441
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PharmacyTY - JOUR AU - Batinić, Bojan AU - Santrač, Anja AU - Jančić, Ivan AU - Li, Guanguan AU - Vidojević, Aleksandra AU - Marković, Bojan AU - Cook, James M. AU - Savić, Miroslav PY - 2017 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2821 AB - We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero. PB - Pergamon-Elsevier Science Ltd, Oxford T2 - International Journal of Developmental Neuroscience T1 - Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide VL - 61 SP - 31 EP - 39 DO - 10.1016/j.ijdevneu.2017.06.001 ER -
@article{ author = "Batinić, Bojan and Santrač, Anja and Jančić, Ivan and Li, Guanguan and Vidojević, Aleksandra and Marković, Bojan and Cook, James M. and Savić, Miroslav", year = "2017", abstract = "We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with alpha 5 GABA(A) receptors (alpha 5GABA(A)Rs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of alpha 5GABA(A)Rs in offspring's preadolescence (from postnatal day 22-28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 mu g/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of alpha 5GABA(A)Rs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of alpha 5GABA(A)Rs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.", publisher = "Pergamon-Elsevier Science Ltd, Oxford", journal = "International Journal of Developmental Neuroscience", title = "Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide", volume = "61", pages = "31-39", doi = "10.1016/j.ijdevneu.2017.06.001" }
Batinić, B., Santrač, A., Jančić, I., Li, G., Vidojević, A., Marković, B., Cook, J. M.,& Savić, M.. (2017). Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. in International Journal of Developmental Neuroscience Pergamon-Elsevier Science Ltd, Oxford., 61, 31-39. https://doi.org/10.1016/j.ijdevneu.2017.06.001
Batinić B, Santrač A, Jančić I, Li G, Vidojević A, Marković B, Cook JM, Savić M. Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. in International Journal of Developmental Neuroscience. 2017;61:31-39. doi:10.1016/j.ijdevneu.2017.06.001 .
Batinić, Bojan, Santrač, Anja, Jančić, Ivan, Li, Guanguan, Vidojević, Aleksandra, Marković, Bojan, Cook, James M., Savić, Miroslav, "Positive modulation of alpha 5 GABA(A) receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide" in International Journal of Developmental Neuroscience, 61 (2017):31-39, https://doi.org/10.1016/j.ijdevneu.2017.06.001 . .