Click to download
Co-administration of atypical and typical antipsychotic agents with a sub-threshold concentration of NMDA potentiates extracellular taurine levels in the rat striatum in vivo We have previously demonstrated that local administration of NMDA significantly enhanced taurine levels in vivo, in rat forebrain regions (Ge et al., 2005a), which agreed with and extended previous reports (Shibanoki et al., 1993). Glycine is required for activity of the NMDA channel, and we have found that co-administration of the glycine re-uptake, GlyT-1, inhibitor Org 25935, which raises glycine levels in the brain, with a sub-threshold concentration of NMDA potentiated taurine levels in the rat striatum (Ge et al., 2005b). This observed potentiation of a sub-effective concentration of NMDA on taurine levels by a GlyT-1 inhibitor further demonstrates the ability of GlyT-1 antagonists to enhance NMDA-mediated neurotransmission. To determine whether the effect of the GlyT-1 antagonist previously described, is common to anti-psychotics currently used in the clinic, various antipsychotics were administered to rats locally perfused by reverse dialysis with a sub-threshold concentration of NMDA and taurine levels measured 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 μm l/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. None of the antipsychotics (i.p.) nor NMDA (50 m M via the microdialysis probe) when given alone, had any effect on taurine levels. However, c o-administration of each with NMDA (50 m M) significantly increased taurine levels (Table 1). Table 1. Effect of several antipsychotics alone and in combination with NMDA on taurine levels in the rat striatum. *p<0.05 t-test vs basal; N/D = not determined
The results show that both atypical and typical antipsychotics can evoke increases in taurine levels when in combination with a sub-threshold concentration of NMDA. The mechanisms of interaction between the antipsychotics tested here, NMDA receptors and modulation of taurine levels are not understood. However, these findings support the hypothesis that potentiation of NMDA function (implied here by enhanced taurine levels) is a common property of anti-psychotic agents. Further experiments are required to determine whether the increase in taurine levels following potentiation of the action of NMDA is fundamental to, or a consequence of, the therapeutic action of antipsychotic agents. Ge, J. et al. (2005b) Br. J. Pharmacol., (this meeting) |
||||||||||||||||||||||||||||||||||||||||||||||
