Faculty Collaboration Database

Positive modulation of α5 GABA_A receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide. Int J Dev Neurosci 2017 Oct;61:31-39

Date

06/15/2017

Pubmed ID

28610974

Pubmed Central ID

PMC5563212

DOI

10.1016/j.ijdevneu.2017.06.001

Scopus ID

2-s2.0-85020699441 (requires institutional sign-in at Scopus site)   14 Citations

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 α5 GABA_A receptors (α5GABA_ARs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABA_ARs 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 6h after LPS treatment (100μg/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 α5GABA_ARs, at a dose (2mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5mg/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 α5GABA_ARs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.

Author List

Batinić B, Santrač A, Jančić I, Li G, Vidojević A, Marković B, Cook JM, Savić MM

Author

James M. Cook PhD University Distinguished Professor in the Chemistry and Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Age Factors
Allosteric Regulation
Amphetamine
Animals
Animals, Newborn
Brain
Central Nervous System Stimulants
Disease Models, Animal
Embryo, Mammalian
Female
GABA Agents
Glutamic Acid
Humans
Lipopolysaccharides
Locomotion
Male
Neurotransmitter Agents
Pregnancy
Prenatal Exposure Delayed Effects
Rats
Receptors, GABA-A
gamma-Aminobutyric Acid