AIM: To investigate neurotoxic effect of L-( + )-2-amino-3-phosphonopropionic acid (L-AP3), a partial agonist/antagonist of metabotropic glutamate receptors (mGluRs), and explore the underlying mechanisms.METHODS: Consciousness and behavior of rats were evaluated after injection of L-AP3, D-( + )-2-amino-3-phosphonopropionic acid ( D-AP3, an isomer of L-AP3)or L-( + )-2-amino-4-phosphonobutyric acid (L-AP4, an agonist of mGluRs) into right caudatum. Brain water,Na + , K + , and Ca2 + contents as well as the permeability of blood brain barrier (BBB) were determined 6 h after treatment of these chemicals. Histological changes at the same time point were also observed. RESULTS: Rats treated with L-AP3 600 nmol but not 60 nmol became somnolentia. Injection of L-AP3 600 nmol induced a great increase of brain water, Na + , and Ca2 + contents,and a decrease of brain K + content ( P ＜ 0.01). Meanwhile, the permeability of BBB was also increased ( P ＜0.01). Electron microscopic study revealed remarkable swelling of astrocytes and degenerative changes of neurons in chemical-treated caudatum. The neurotoxic effect of L-AP3 was not mimicked by D-AP3 or L-AP4 ( P ＜0.05). DL-2-Amino-5-phosphonovaleric acid, an antagonist of N-methyl-D-aspartate (NMDA) receptors,attenuated the changes induced by L-AP3 ( P ＜ 0.05),whereas ( ± )-α-methyl-( 4-carboxyphenyl ) glycine, a non-subtype specific antagonist of mGluRs, failed to block the effect of L-AP3. CONCLUSION: Intracaudatal injection of L-AP3 induced neurotoxic effect characterized by vasogenic brain edema, neuronal degeneration,and high brain Ca2+ content. Neurotoxic effect of L-AP3 was stereoselective and might be mediated by phospholipase C activation and partially involvement of NMDA receptors.