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

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 GABAA receptors (α5GABAARs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABAARs in offspring’s preadolescence (from postnatal day 22 to 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 μg/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 α5GABAARs, 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 α5GABAARs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.

Synthesis of chiral GABAA receptor subtype selective ligands as potential agents to treat schizophrenia as well as depression

“…The effects on male mice in the same paradigm were very weak or none at all. 26 Furthermore, analogs of 4(R)-CH 3 enantiomer 1, such as the methyl amide MP-III-022, 27 the carboxylic acid SH-053-2'F-R-CH 3 -acid 28 , etc., which are more potent at the α5-subtype than 1, have also been investigated and undergone a number of behavioral studies. In order to study how the chirality at the C-4 position of IBZD could affect the pharmacological response, the enantiomer of 1, SH-053-2'F-S-CH 3 (2) was synthesized.…”

“…Carboxylic acid 6 exhibited excellent properties in all three assays, however, the acid functionality will prevent the penetration of the blood brain barrier which was demonstrated for the R enantiomer. 27 This property is not suitable for the treatment of schizophrenia and depression. Cognitive deficits developed in these two disease states are still poorly managed with current drugs.…”

“…43 The previous results indicated that replacement of ester functions by substituted 1,2,4-oxadiazoles 36,44 significantly increased the in vitro and in vivo stability, as well as slightly improved the hydrophilicity of the ligands. 19 Moreover, the efficacy at BZD receptors was enhanced as compared to the corresponding ester ligands.…”

“…Additionally, it must be pointed out that the acid 6 was synthesized not only because it was an important intermediate for the majority of the analogs, but also because the enantiomer (R)-CH 3 carboxylic acid in the C(4)R-isomer series significantly increased the α5-subtype selectivity and potency. 27 It was hoped that the acid 6 in the C(4)Sisomer series might affect a similar increase on the selectivity and potency at the α2/α3/α5-subtype. 5b-5e 5b R 2 = CH 2 CH 2 CH 3 (GL-I-32), 82% 5c R 2 = CH(CH 3 ) 2 (GL-I-31), 97% 5d R 2 = C(CH 3 ) 3 (GL-I-30), 96% 5e R 2 = C(CH 3 ) 2 CH 2 CH 3 (GL-I-33), 77% Scheme 3.…”

“…This process gave methyl oxadiazole GL-I-65 (9a), ethyl oxadiazole GL-I-66 (9b) and isopropyl oxadiazole GL-I-81 (9c) in improved yields of 79-85%, respectively, as depicted in Scheme 5. To explore the extent of flexibility of the hydrogen-bond acceptor in the binding pocket designed H1 in the pharmacophore/receptor model (see Figure S1 in Supplementary material), 22,36 it was decided to synthesize a linear nitrile at the C(3) position, which has sometimes been employed to increase water solubility of a ligand and has also been used to reduce possible oxidative metabolism by the liver in clinical studies. 45 The nitrile MP-III-018.A (10) The characterization of the lead compound 2 was being carried out simultaneously with the synthesis and assessment of the novel analogs.…”