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. 2023 Oct 2:15:281-286.
doi: 10.1016/j.ibneur.2023.09.012. eCollection 2023 Dec.

Effects of gestational haloperidol exposure on mRNA expressions related to glutamate and GABA receptors in offspring

Affiliations

Effects of gestational haloperidol exposure on mRNA expressions related to glutamate and GABA receptors in offspring

Hiroshi Kumon et al. IBRO Neurosci Rep. .

Abstract

Antipsychotic treatment is vital for patients with schizophrenia even in the perinatal period, but the impact at the molecular biological level on offspring is unclear. The aim of the present study was to investigate the effects of intraperitoneal haloperidol injection to pregnant mice on glutamate and GABA receptors in the brain of offspring mice. Eight-week-old pregnant mice were treated with either intraperitoneal haloperidol or normal saline injection, and their offspring were defined as F1 mice. In addition, eight-week-old male mice were used as acute mice that were intraperitoneally injected with haloperidol or normal saline for 20 days. mRNA expression levels were measured by RT-qPCR. Western blotting was performed of the frontal lobes of F1 mice. In the hippocampi of F1 mice, Grik3 (p = 0.023) and Gabra3 (p = 0.004) mRNA expression levels were significantly higher in the haloperidol group than in the control group, whereas Gria2 (p < 0.001) and Grin2a (p < 0.001) mRNA expression levels were significantly lower in the haloperidol group than in the control group. Gria2 (p = 0.015), and Grik3 (p = 0.037), and Grin2a (p = 0.012) mRNA expression levels were significantly lower in the haloperidol group than in the control group in the frontal lobes of F1 mice. In the hippocampi of acute mice, Grik3 (p = 0.049) and Gabra3 (p = 0.007) mRNA expression levels were significantly decreased in the haloperidol group. Fetal exposure to haloperidol can affect glutamate and GABA receptors through mRNA expression changes in the brain of offspring.

Keywords: GABA receptor; Glutamate receptor; Haloperidol; Pregnant.

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Conflict of interest statement

No potential conflict of interest relevant to this article was reported.

Figures

Fig. 1
Fig. 1
The mRNA expression levels in the hippocampi of F1 mice of the haloperidol and control groups. HAL: Offspring of mice intraperitoneally injected with HAL during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. Control: Offspring of mice that were intraperitoneally injected with normal saline during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. Average differences in mRNA expression levels between the two groups were assessed by Student’s t-test or the Mann–Whitney U test. The data are shown as *p < 0.05, * *p < 0.01, * **p < 0.001. n = 6 for the HAL group and n = 8 for the control group.
Fig. 2
Fig. 2
The mRNA expression levels in the frontal lobes in the haloperidol and control groups of F1 mice. HAL: Offspring of mice that were intraperitoneally injected with HAL during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. Control: Offspring of mice that were intraperitoneally injected with normal saline during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. Average differences in mRNA expression levels between the two groups were assessed by Student’s t-test or the Mann–Whitney U test. The data are shown as ∗p < 0.05. n = 6 for the HAL group and n = 8 for the control group.
Fig. 3
Fig. 3
The mRNA expression levels in the temporal lobes of the haloperidol and control groups of F1 mice. HAL: Offspring of mice that were intraperitoneally injected with HAL during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. Control: Offspring of mice that were intraperitoneally injected with normal saline during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. Average differences in mRNA expression levels between the two groups were assessed by Student’s t-test or the Mann–Whitney U test. n = 6 for the HAL group and n = 8 for the control group.
Fig. 4
Fig. 4
The mRNA expression levels in (A) the hippocampi and (B) frontal lobes of the haloperidol and control groups of acute mice. HAL: Male mice that were intraperitoneally injected with 1 mg/kg/day HAL for 20 days from 8 weeks after birth. Control: Male mice that were intraperitoneally injected with 1 mg/kg/day normal saline for 20 days from 8 weeks after birth. Average differences in mRNA expression levels between the two groups were assessed by Student’s t-test or the Mann–Whitney U test. The data are shown as ∗p < 0.05, ∗∗p < 0.01. n = 8 for each group.
Fig. 5
Fig. 5
The protein expression levels of GRIK3 in the frontal lobes of F1 mice measured by Western blotting. HAL 1–6: Offspring of mice that were intraperitoneally injected with HAL during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. Control 1–8: Offspring of mice that were intraperitoneally injected with normal saline during pregnancy at 1 mg/kg/day from pregnancy day 1 to birth. The protein expression levels of glutamate receptor, ionotropic, kainate 3 (GRIK3) (104 kDa), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (36 kDa) were evaluated by Western blotting. Average differences of GRIK3 and GAPDH between the two groups were assessed by the Mann–Whitney U test. The data are shown as means ± SEM. ∗∗∗p < 0.001.

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