Concentration-dependent changes in motor behavior produced by continuous intrathecal infusion of excitatory amino acids in the rat spinal cord

Abstract

A growing body of evidence has suggested that glutamate receptors mediate selective degeneration of neurons in the central nervous system during the development of neurodegenerative diseases [1,2,4,14,17,18,20]. Glutamate receptors are divided into N-methyl-D-aspartate (NMDA)-type and non-NMDA-type. Neurotoxicity mediated by the latter has attracted much interest as a possible causative mechanism underlying amyotrophic lateral sclerosis (ALS) [5,15]. As the clinical course of ALS is chronic and progressive, investigation of chronic effects of non-NMDA receptor agonists on neuronal function would be useful for evaluating the role of glutamate receptor-mediated neurotoxicity in ALS. However, chronic non-NMDA receptor- mediated neurotoxicity has been investigated less thoroughly than acute neurotoxicity [3,7-9,11-13,16,19]. We infused an aqueous solution of R,S-α- amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) intrathecally and continuously by an osmotic minipump in rats. This method of continuous infusion enabled us to keep the drag concentration relatively constant in the cerebrospinal fluid surrounding the spinal cord. The present method of AMPA administration is more suitable for investigating ALS pathogenesis than acute injections, in view of the gradual progression of the disease and the selectivity of lesions produced.