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    • Acknowledgements br Introduction The neurotransmitter

    2022-06-09

    Acknowledgements
    Introduction The neurotransmitter glycine acts through two receptors: a strychnine-sensitive glycine receptor (GlyA) and a strychnine-insensitive glycine receptor (GlyB). GlyA is localized to the neuronal membrane post-synaptic to inhibitory glycinergic neurons, whereas GlyB is associated with the NR1 subunit of the excitatory N-methyl-D-aspartate (NMDA) receptor (Kuryatov et al., 1994; Legendre, 2001). Glycine therefore has bidirectional actions on neuronal excitability. The extracellular concentration of glycine is regulated by glycine transporter 1 (GlyT1) and glycine transporter 2 (GlyT2) (Aragón and López-Corcuera, 2005). GlyT1 is expressed on glial cells and glutamatergic neurons (Cubelos et al., 2005, Raiteri and Raiteri, 2010), whereas GlyT2 is predominantly expressed at glycinergic nerve terminals (Jursky and Nelson, 1995). NMDA receptor function is enhanced in the hippocampus of GlyT1 heterozygous-knockout mice, suggesting that GlyT1 regulates the concentration of glycine at NMDA receptor-containing excitatory synapses (Gabernet et al., 2005). Thus, GlyT1 inhibitors likely promote NMDA receptor function. GlyT1 inhibitors may have anxiogenic actions, because NMDA receptor activation induces anxiety-like behavior in mice (Miguel and Nunes-de-Souza, 2008). However, GlyT1 inhibitors may also have anxiolytic actions, because SSR504734, a GlyT1 inhibitor, both attenuates the acquisition and expression of contextual conditioned fear in rats (Nishikawa et al., 2006) and decreases maternal separation-induced ultrasonic vocalization (USV) in rat pups (Depoortère et al., 2005). Furthermore, the NMDA receptor antagonists MK-801 and DL-amino-5-phosphonovaleric Dexlansoprazole receptor (AP5) have been shown to have anxiolytic actions in rats (Kehne et al., 1991), and 7-chlorokynurenic acid (7-Cl-KYN), a GlyB antagonist, has been shown to have anxiolytic actions in mice (Trullas et al., 1989). Together, these reports suggest that the anxiolytic action of GlyT1 inhibitors is not induced by activation of GlyB. However, which glycine receptor subtype is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be fully elucidated. Recently, it was reported that the hyperlocomotion induced by a GlyT1 inhibitor in mice was antagonized by the GlyA antagonist strychnine (Kopec et al., 2010), suggesting that not only GlyB but also GlyA plays a significant role in the behavioral changes induced by GlyT1 inhibitors. Rodent pups emit USVs (peak frequency around 40kHz) when they are separated from their mother and littermates (Brudzynski et al., 1999, Zippelius and Schleidt, 1956). Because clinically proven anxiolytics such as the benzodiazepines and selective serotonin reuptake inhibitors reduce the number of maternal separation-induced USVs in rat pups, USV is thought to be a predictive animal model of the anxiolytic effect (Insel et al., 1986, Winslow and Insel, 1991). Therefore, in the present study, maternal separation-induced USV in rat pups was used as an index of anxiety.
    Materials and methods
    Results
    Discussion Maternal separation-induced USV is a well-established index of anxiety in rodents (Olivier et al., 1998a, Olivier et al., 1998b, Winslow et al., 1990). In agreement with previous reports, we showed that diazepam and escitalopram, which are clinically proven anxiolytics, significantly decreased USV, which suggests that the USV test may be predictive of anxiolytic effect in humans. We also confirmed previously published data showing that SSR504734 significantly decreases USV (Depoortère et al., 2005). We also evaluated another GlyT1 inhibitor, ALX5407, which has a different chemical structure from that of SSR504734. ALX5407 decreased USV when administered at a dose of 1mg/kg; however, it has been reported that ALX5407 does not have anxiolytic actions at a dose of 3 or 10mg/kg, as assessed by behavioral tests in adult rats (Harsing et al., 2003). These inconsistent results may be explained by the different pretreatment times and routes of administration used in the studies. Harsing et al. (2003) administered ALX5407 intraperitoneally 30min prior to conducting the tests, whereas we orally administered it 3h prior to conducting the tests. Because ALX5407 has an amino acid moiety within its structure (Atkinson et al., 2001), we predicted that its penetration into the brain would be slow. Indeed, in a microdialysis study, extracellular glycine levels gradually increased, reaching peak levels in the prefrontal cortex at 3h and in the cerebellum at 6h after oral administration of 10mg/kg (±)-NFPS, a racemic form of ALX5407 (Perry et al., 2008). Kinney et al. (2003) demonstrated that intraperitoneal administration of ALX5407 (1mg/kg) 2h prior to the test increased the degree of prepulse inhibition in mice. Thus, it may be possible to detect the anxiolytic actions of ALX5407 by taking the pharmacokinetics of ALX5407 and pharmacodynamics of glycine in the brain into account.