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, 500.0nmol/4microl), 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 (250.0nmol/4microl). Locomotion induced by the N-methyl-D-aspartate-receptor antagonist dizocilpine (0.08, 0.16, 0.32mg/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, 3.0mg/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.
Kronthaler
U O
UO
Aventis Behring GmbH, Marburg, Federal Republic of Germany. Ulrich.Kronthaler@aventis.com
Schmidt
W J
WJ
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000502:physiology; D005106:Exploratory Behavior / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000502:physiology*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
D011954:Receptors, Dopamine; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate