AMPA RECEPTOR-MEDIATED SLOW NEURONAL DEATH IN THE RAT SPINAL-CORD INDUCED BY LONG-TERM BLOCKADE OF GLUTAMATE TRANSPORTERS WITH THA

Excitotoxicity secondary to the loss of glutamate transporters (GluT) has been proposed as a possible pathogenetic mechanism for neuronal de generation in amyotrophic lateral sclerosis. We therefore investigated whether prolonged in vivo pharmacologic inhibition of GluT would resu lt in neuronal damage in the rat. DL-Threo-beta-hydroxyaspartate (THA) , a potent GluT inhibitor, and glutamate were continuously infused int o the rat spinal subarachnoid space by using a mini-osmotic pump. Anim als that received both THA and glutamate, but not those received eithe r singly, displayed tail paralysis with or without hind-limb paralysis and urinary incontinence after the third postoperative day. Pathologi cally, symptomatic animals exhibited neuronal loss with a variable ext ent of gliosis preferentially involving the dorsal horn of the lumbosa cral cord. In the rostral spinal segments adjacent to those regions of intense pathologic changes, small neurons in the dorsal horn were sel ectively destroyed, a pattern similar to the late-onset neuronal damag e induced by continuous intrathecal administration of 1-amino-3-hydrox y-5-methyl-4-isoxazole propionic acid (AMPA) [R. Nakamura et al., Brai n Res. 654 (1994) 279-285]. These behavioral and pathologic changes we re blocked by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), suggesting that pharmacologic blockade of GluT causes selective neuronal damage i n vivo by AMPA receptor activation. (C) 1997 Elsevier Science B.V.