Glycine transporter (GlyT1) inhibitors with reduced residence time increase prepulse inhibition without inducing hyperlocomotion in DBA/2 mice

Prepulse inhibition of the startle reflex and response to antipsychotic treatments in two outbred mouse strains in comparison to the inbred DBA/2 mouse

“…By comparison, DBA/2 mice increased PPI in response to thioperamide, ciproxifan, and ABT-239 (Browman et al 2004;Fox et al 2005). GlyT1 inhibitors similarly showed different effects on PPI in DBA/2 versus C57BL/6 mice, with ALX-5407, (S)-13h, SSR504734, SSR103800, sarcosine, and Roche-7 all increasing PPI in DBA/2 mice (Kinney et al 2003;Depoortère et al 2005;Lindsley et al 2006;Boulay et al 2008;Kopec et al 2010). In C57BL/6 mice, ALX-5407 significantly reduced PPI at 10 and 15 mg/kg (Lipina et al 2005).…”

“…In addition to increasing PPI after treatment with typical and atypical antipsychotics, DBA/2 mice have increased PPI in response to treatment with several H 3 R antagonists and GlyT1 inhibitors (Kinney et al 2003;Browman et al 2004;Depoortère et al 2005;Fox et al 2005;Lindsley et al 2006;Boulay et al 2008;Kopec et al 2010). Treatment with H 3 R antagonists and a GlyT1 inhibitor in other mouse strains was negative, except when PPI was reduced by apomorphine or MK-801 (Browman et al 2004;Lipina et al 2005;Ligneau et al 2007).…”

“…While both the DBA/2 and C57BL/ 6 mouse strains have been useful in PPI studies for identifying typical and atypical antipsychotics, only the DBA/2 strain has responded to therapeutics with other mechanisms of action. DBA/2 mice increased PPI after treatment with mood stabilizers (Flood et al 2009) and GlyT1 inhibitors (Kinney et al 2003;Depoortère et al 2005;Lindsley et al 2006;Boulay et al 2008;Kopec et al 2010). Mood stabilizers are used in treating both bipolar depression and schizophrenia and the GlyT1 inhibitor sarcosine has shown efficacy in small clinical trials (Tsai et al 2004;Lane et al 2005).…”

“…A phase II clinical trial with the potent GlyT1 inhibitor, RG1678, demonstrated improvements in negative symptoms of schizophrenia (Lindsley 2010;Pinard et al 2010). Several H 3 R antagonists and GlyT1 inhibitors increased PPI in the DBA/2 mouse (Kinney et al 2003;Browman et al 2004;Depoortère et al 2005;Fox et al 2005;Lindsley et al 2006;Boulay et al 2008;Kopec et al 2010), suggesting that the DBA/2 model of naturally low PPI may be broadly predictive of antipsychotic activity for compounds with novel mechanisms of action.…”

Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups

“…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 40 kHz) when they are separated from their mother and littermates (Brudzynski et al, 1999;Zippelius and Schleidt, 1956).…”