Search

2-Chloro-N-S-phenyl 2S-piperidin-2-yl methyl]-3-trifluoromethyl benzamide, monohydrochloride (SSR504734) is a potent and selective inhibitor of the glycine transporter type 1, which increases central N-methyl-D aspartate glutamatergic tone. Since glutamate has been shown to play a role in the regulation of the dopaminergic system in dopamine-related disorders, such as schizophrenia, we investigated the possibility that SSR504734 may modify the basolateral amygdala-elicited stimulation of dopamine release in the nucleus accumbens via an augmentation of glutamate receptor-mediated neurotransmission. First, our data confirmed that SSR504734 is an inhibitor of GlytT1. In the nucleus accumbens of anesthetized rat, SSR504734 (10 mg/kg, i.p.) induced an increase of extracellular levels of glycine as measured by microdialysis coupled with capillary electrophoresis with laser-induced fluorescence detection. Second, the data demonstrated that SSR504734 (10 mg/kg, i.p.) enhanced the facilitatory influence of glutamatergic afferents on dopamine neurotransmission in the nucleus accumbens. Using an electrochemical technique, we measured dopamine release in the nucleus accumbens evoked by an electrical stimulation of the basolateral amygdala. SSR504734 facilitated dopamine release evoked by a 20 or a 40 Hz frequency basolateral amygdala stimulation. This facilitatory effect was dependent on glutamatergic tone, as intra-nucleus accumbens application of 6-7-dinitroquinoxaline-2,3-dione (10(-3) M) or DL-2-amino-5-phosphonopentanoic acid (10(-3) M), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D aspartate receptors antagonists, respectively, inhibited dopamine release evoked by basolateral amygdala stimulation. Furthermore DL-2-amino-5-phosphonopentanoic acid co-administrated with SSR504734 hampered the dopamine-evoked release facilitation. These data underline the in vivo implication of the glycine uptake mechanism in the control of subcortical glutamate/dopamine interactions.

In vivo microdialysis was used to investigate the interactions between dopamine (DA), glutamate (Glu) and aspartate (Asp) in anaesthetised-rat striatum. The combination of brain microdialysis and capillary electrophoresis with laser-induced fluorescence detection (CE-LIFD) allows the simultaneous monitoring of the efflux of these neurotransmitters up to every 10 s. DA and Glu reuptake inhibitors, nomifensine and L-trans-pyrrolidine-2,4-dicarboxylic acid (PDC) and, dopaminergic and glutamatergic receptor agonists, apomorphine and NMDA respectively, were administered by reverse dialysis. Reverse dialysis of 20 micro M nomifensine induced a rapid and marked increase (+3200% at 5 min) in extracellular DA, while a decrease in Glu and Asp (-11 and -25%, respectively) was observed simultaneously. Reverse dialysis of 10 micro M apomorphine led to progressive changes: -63% decrease in DA and +25% Glu increase at 36 min. Reverse dialysis of 1 mM NMDA induced a simultaneous increase in DA, Glu and Asp which peaked at +2 min (+840%, +40% and +150%, respectively). Surprisingly, a second increase in Glu was observed 5 min after the end of NMDA perfusion. Reverse dialysis of PDC (1 mM and 10 mM) induced a rapid increase in Glu and Asp levels, while DA increased with a 26-s delay. These findings indicate that, in the striatum, endogenous DA and Glu may act in opposition to regulate each other's efflux. These results have been obtained due to unique features offered by microdialysis coupled with CE-LIFD.

The present study investigated in vivo the kinetic of the changes in rat striatal extracellular concentrations of dopamine (DA), and its monoamine oxidase (MAO)-derived metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), following administration either of nitric oxide (NO) synthase (NOS) inhibitors 7-nitroindazole (7-NI) and Nomega-nitro-l-arginine methyl ester (L-NAME) or of the widely used MAO inhibitor pargyline. DA and DOPAC concentrations were determined every 4 min by microdialysis combined with capillary zone electrophoresis coupled with laser-induced fluorescence detection (CZE-LIFD) and by differential normal pulse voltammetry (DNPV), respectively. Administration of 7-NI, both systemic (30 mg/kg, intraperitoneally, i.p.) or intrastriatal (1 mM through the microdialysis probe), as well as administration of pargyline (75 mg/kg, i.p.), induced simultaneously in the striatum a significant increase in extracellular DA and a significant decrease in extracellular DOPAC. However, administration of L-NAME (200 mg/kg, i.p.) produced a significant increase in striatal extracellular DA without changes in extracellular DOPAC. These data suggest a possible MAO inhibitory effect of 7-NI which seems to be restricted to this NOS inhibitor. These results may be of special interest for the studies on functional role of NO in the brain, particularly in dopaminergic transmission.