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

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.