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-isoxazolepropionate (AMPA) was investigated by infusing this agent continuously for 7 days intrathecally to adult rats using a mini-osmotic pump. Behavioral changes were apparent only after the second postoperative day, when the rats displayed hindlimb palsy or incontinence of urine. The behavioral deficits became progressively severe and the rats usually displayed both hindlimb paraplegia and incontinence of urine by the 7th postoperative day. These progressive behavioral deficits were induced in a dose-dependent manner in the rats that received AMPA at a dose of > 100 pmol/h (100 microM at 1 microliter/h, 17 nmol in total dose). The severity of behavioral deficits was in parallel with that of neuropathological changes in the lumbosacral cords. In spinal segments rostrally adjacent to those with severe pathological changes, only the neurons in the dorsal horns (Rexed's laminae II-IV) were destroyed with intense gliosis. These changes were not induced by infusing AMPA for 1 day. The concomitant 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 neuropathological changes. The findings of the present study suggest that this late-onset, selective neurotoxicity is mediated by AMPA-type glutamate receptors.