Neurotoxicity of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (
DCG-IV), a potent agonist for
metabotropic glutamate receptors negatively coupled to
adenylyl cyclase, was investigated in vivo by the intraventricular administration in the rat, compared with that of (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (
L-CCG-I) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic
acid [(1S,3R)-ACPD]. Neither
L-CCG-I nor (1S,3R)-ACPD caused any apparent pathological change in the brain at an intraventricular dose of 1 mumol, whereas
DCG-IV induced selective neuronal damage in some rats at higher doses than 3 nmol. The neurotoxicity was intensified in a dose-dependent manner, and at a dose of 50 nmol
DCG-IV caused repetitive
seizures and selective neuronal damage in all cases. Neuronal damage was pronounced in the cingulate cortex, lateral septum and hippocampus, and a few degenerating neurons were observed also in other brain areas, such as the striatum, thalamus or neocortex. Since
DCG-IV activates
N-methyl-D-aspartate-type receptors as well at relatively high concentrations, the protective effect of a competitive antagonist for
N-methyl-D-aspartate receptors, 3-[(RS)-2-carboxypiperazin-4-yl]propyl-1-
phosphonic acid (
CPP), was examined on the neurotoxicity of
DCG-IV. Although a combined treatment with
CPP (0.1 nmol) completely blocked the neurotoxicity of
N-methyl-D-aspartate (100 nmol), at least 3 nmol of
CPP was necessary to decrease the neurotoxicity of
DCG-IV (50 nmol) to a considerable extent. The synergistic activation of
metabotropic glutamate receptors and
N-methyl-D-aspartate receptors is suggested as a possible mechanism underlying the selective neuronal damage induced by
DCG-IV, although a direct participation of
metabotropic glutamate receptors in
glutamate neurotoxicity is not deniable.