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.