On the role of inhibitory glutamate receptors in N-methyl-D-aspartate- and dopamine-receptor mediated motor behavior of rats

The physiological function of inhibitory group II metabotropic glutamate-receptors, a family of second messenger coupled glutamate-receptors, for motor behavior is almost unknown. The aim of this study is to address this topic by quantifying motor effects of the preferential group II agonist (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine, administered i.c.v. (62.5, 125.0, 187.5, 250.0, 500.0 nmol/4 mu l), in an open-field equipped with a hole-board. (2S,3S,4S)-alpha-(carboxycyclopropyl) -glycine decreased spontaneous locomotor and exploratory behavior, which was blocked be the group II antagonist (2S)-alpha-ethylglutamic acid (250.0 nmol/4 mu l). Locomotion induced by the N-methyl-D-aspartate-receptor antagonist dizocilpine (0.08, 0.16, 0.32 mg/kg) was counteracted by the group II agonist (2S,3S,4S)-alpha- (carboxycyclopropyl) -glycine, but an antagonism towards dizocilpine did not occur in all aspects of motor behavior evaluated. In contrast to the antagonism of dizocilpine induced locomotion, D,L-amphetamine (1.0, 2.0, 3.0 mg/kg) induced locomotion was not antagonised by (2S,3S,4S)alpha-(carboxycyclopropyl)-glycine. The results suggest that group II agonists may be devoid of psychotomimetic effects in humans and even may antagonise this side effect of N-methyl-D-aspartate receptor antagonists. Since group II activation and N-methyl-D-aspartate-receptor blockade very efficiently protects against excitotoxic neurodegeneration, selective group II agonists may allow novel pharmacotherapeutical approaches in pathophysiological conditions characterised by a glutamatergic hyperactivity, like epilepsy, ischemia and trauma.