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Abstract: 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 (10mg/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 (10mg/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 40Hz 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), α-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. [Copyright &y& Elsevier]

Abstract: Arginine vasopressin and corticotropin-releasing factor are two neuroactive peptides that regulate hypothalamic–pituitary-axis and associated stress response. While the potential antidepressant and anxiolytic profiles of corticotropin-releasing factor 1 antagonists have been well studied, the concept of blockade of vasopressin system as another approach for the treatment of emotional processes has only been made available recently by the synthesis of the first non-peptide antagonist at the V1b receptor, SSR149415. In the present study SSR149415 has been compared with the corticotropin-releasing factor 1 antagonist SSR125543 and with anxiolytic and antidepressant drugs on the response of hippocampal cholinergic and cortical noradrenergic systems to the anxiogenic benzodiazepine receptor inverse agonist FG 7142. Acute (0.3–10 mg/kg, i.p.) and long-term administration (10 mg/kg, i.p., 21 days) of SSR149415 and SSR125543 reduced the FG 7142-induced increase in extracellular concentrations of acetylcholine in the hippocampus of anesthetized rats measured by microdialysis. By contrast acute and long-term administration of SSR149415 failed to reduce the FG 7142-induced increase in the release of norepinephrine in the cortex of freely moving rats. The present results demonstrate that the two compounds have similar profiles in a model of activation by an anxiogenic drug of the hippocampal cholinergic system and they suggest that SSR149415 and SSR125543 may have anti-stress anxiolytic and antidepressant effects via a mechanism of action different from classical benzodiazepine ligands and noradrenergic antidepressants. [Copyright &y& Elsevier]

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 μM 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 μM 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. [Copyright &y& Elsevier]