LATE-ONSET SELECTIVE NEURONAL DAMAGE IN THE RAT SPINAL-CORD INDUCED BY CONTINUOUS INTRATHECAL ADMINISTRATION OF AMPA

Neurotoxicity mediated by 1-amino-3-hydroxy-5-methyl-4-isoxazolepropio nate (AMPA) was investigated by infusing this agent continuously for 7 days intrathecally to adult rats using a mini-osmotic pump. Behaviora l changes were apparent only after the second postoperative day, when the rats displayed hindlimb palsy or incontinence of urine. The behavi oral deficits became progressively severe and the rats usually display ed both hindlimb paraplegia and incontinence of urine by the 7th posto perative day. These progressive behavioral deficits were induced in a dose-dependent manner in the rats that received AMPA at a dose of > 10 0 pmol/h (100 mu M at 1 mu l/h, 17 nmol in total dose). The severity o f behavioral deficits was in parallel with that of neuropathological c hanges in the lumbosacral cords. In spinal segments rostrally adjacent to those with severe pathological changes, only the neurons in the do rsal horns (Rexed's laminae II-IV) were destroyed with intense gliosis . These changes were not induced by infusing AMPA for 1 day. The conco mitant administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist for non-N-methyl-D-aspartate (NMDA) receptors, with AMPA , but not that of 2-amino-5-phosphonovalerate (APV), an antagonist for NMDA receptor, prevented induction of the behavioral and neuropatholo gical changes. The findings of the present study suggest that this lat e-onset, selective neurotoxicity is mediated by AMPA-type glutamate re ceptors.