Approximately 1 in 10,000 adults develops schizophrenia characterized by positive symptoms, negative symptoms, and cognitive disfunction each year (Häfner & an der Heiden, 1997). Schizophrenia patients have over a two-fold risk of dying and thus a short life expectancy, approximately 20 years less than the general population (McGrath et al., 2008) (Laursen et al., 2014) (Auquier et al., 2007). Antipsychotic treatment is vital even in the perinatal period for schizophrenia patients to prevent relapse. However, antipsychotics could increase the risk of congenital malformations or withdrawal-emergent syndrome including tremor, irritability, and somnolence (Gentile, 2010) (Coppola et al., 2007). In this regard, some evidence is available at the phenotype level, but the impact at the molecular biological level on offspring is unclear.
The glutamate and dopamine hypotheses have been considered among the pathologies of schizophrenia. Those neurotransmitters are especially relevant to positive symptoms (Howes et al., 2015) (Javitt, 2007) (Javitt, 2010). Several studies have investigated the association of schizophrenia with glutamine and gamma-aminobutyric acid (GABA) receptors (Kilic et al., 2010) (Gardoni et al., 2008) (Itoh, 1983) (Ziólkowska & Höllt, 1993). It has been suggested that one of the glutamine receptors, the N-methyl-d-aspartate (NMDA) receptor, is strongly related to symptoms of schizophrenia because phencyclidine, a noncompetitive NMDA agonist, induces emotional and cognitive deficits in schizophrenia (Javitt et al., 2012) (Nabeshima et al., 2006) (Mouri et al., 2007). Moreover, the meta-analyses reported that polymorphisms of GRIK3, the principal subunit of the kainate-type ionotropic glutamate receptor, increased schizophrenia risk by 30% (Dai et al., 2014). Antipsychotics have been developed based on the various neurotransmitter hypotheses such as dopamine, serotonin, glutamate, glycine, cannabidiol, and estrogen (Maric et al., 2016) (Stępnicki et al., 2018).
Some first-generation antipsychotics including haloperidol (HAL) and many second-generation antipsychotics have been used to treat schizophrenia (Stępnicki et al., 2018). Although the main mode of action of HAL is as an antagonist of the D2 dopamine receptor (Nyberg et al., 1995), it has also antagonistic actions for the NMDA receptor (Zhuravliova et al., 2007) and the sigma-1 receptor (Dalwadi et al., 2017). Six-month HAL administration increased glutamine and total GABA levels in forebrain tissue in rats (Konopaske et al., 2013), and HAL induced neurotoxic effects resulting in neuronal death (Nasrallah & Chen, 2017).
It has been reported that the transplacental transfer rate of HAL was 65.5% in humans (Newport et al., 2007). In a cohort study, gestational HAL exposure increased the risk of fetal loss from 22.2% in the 3–6 months prior to conception to 78.6% with first trimester exposure (Boland et al., 2017). Although the transplacental transfer rate in the mouse is unknown, intraperitoneal HAL injection to pregnant mice induced recognition memory deficits and impaired the proliferation and maturation of adult-born dentate granule cells in offspring (Wang et al., 2019). With respect to intraperitoneal HAL injection to pregnant mice, HAL more easily leaves and enters into the brain in the fetal circulation because it contains less protein than the maternal circulation (Seeman, 2004). Moreover, it has been reported that mRNA expressions of dopamine D2 and D3 receptors in the prefrontal cortex (PFC), hippocampus, and nucleus accumbens were increased in adult rats treated by methylazoxymethanol acetate, a neurotoxin that reduces DNA synthesis, which is used as a schizophrenia model (Stark et al., 2020).
The aim of the present study was to investigate the effects of intraperitoneal HAL injection to pregnant mice on glutamine and GABA receptors in the brain of offspring mice.