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Glycine re-uptake glyt-1 inhibitor ORG 25935 potentiates NMDA induced taurine levels in the rat striatum in vivo Glycine is a well-characterised simple amino acid neurotransmitter in the CNS and acts as a necessary co-agonist for NMDA receptors and thus modulates NMDA-dependent excitatory neurotransmission (Sur et al., 2004). In the forebrain, synaptic glycine levels are regulated by the glycine transporter, GlyT-1. Org 25935 has been demonstrated to be a selective GlyT-1 inhibitor and to increase glycine levels in rat forebrain regions (Ge et al., 2001). It has been reported that blockade of GlyT-1 potentiates NMDA receptor function in vitro and in vivo (Bergeron et al., 1998; Kinney et al., 2003). In the present study, we demonstrate that NMDA increases taurine levels in vivo, in the frontal cortex in a concentration dependent manner. Furthermore, co-administration of Org 25935 with a sub-effective concentration of NMDA enhances taurine levels in the rat striatum. Male rats (Wistar, 250 - 300 g, Harlan) were anaesthetised using 3% isoflurane/95% oxygen and guide cannulae were stereotaxically implanted . After at least a one week recovery period, a microdialysis probe (4 mm membrane) was inserted into the striatum (mm, A -0.8, L -3.0, V -4.5, relative to Bregma), and perfused with artificial cerebrospinal fluid (aCSF) at 2 μl/min 18 hr before the experiments commenced. Dialysate samples were collected every 20 min, and the taurine levels were analysed by HPLC coupled with fluorescence detection. Local administration of NMDA (50 μM, via the microdialysis probe) non significantly increased taurine levels by some 20 to 25 % above the basal levels (p>0.05 t-test). Local (10 μM) and systemic (5 & 10 mg kg-1 i.p.) administration of Org 25935 alone, failed to modify taurine levels (Table 1). However, both local and systemic co-administration of Org 25935 with NMDA (50 μM) significantly enhanced taurine levels in a bell shaped manner (Table 1).
Table 1. Effect of Org 25935 and its combination with NMDA on taurine levels in the rat striatum. * P<0.05 t test; N/D = not determined The present study demonstrates that the GlyT-1 inhibitor Org 25935, potentiates NMDA function, indicated by enhanced levels of taurine in the rat striatum following co-administration with NMDA. The significance of such a rise in taurine is not clear because the physiological and pharmacological functions of taurine are poorly understood. However, if a hypoglutamatergic state is responsible for the manifestation of some of the symptoms of schizophrenia, then the potentiation of NMDA receptor function by Org 25935 may be evidence of a mechanism by which GlyT-1 inhibitors may have a therapeutic effect in schizophrenia.
Bergeron, R. et al. (1998) Proc. Natl. Acad. Sci., 95, 15730-15734. |
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