The effect of local application of homocysteine on neuronal activity in the central nervous system of the rat.

Homocysteine, a monocarboxylic, sulfur-containing amino acid, produces convulsions in rats and mice when administered systemically. Convulsions and high serum concentrations of homocysteine are among the symptoms that characterize patients with homocystinuria, a hereditary disorder of amino acid metabolism. In order to evaluate the effects of homocysteine on the central nervous system directly, extracellular recordings were made from neurons in rat cerebral cortex, cerebellum and midbrain during local application of homocysteine by pressure ejection or iontophoresis. Both methods of drug delivery produced dose-dependent increases in the activity of neurons in every area tested. Activity was increased by D,L-homocysteine and L-glutamate in 67 percent of cells tested with both drugs. The doses required to produce equivalent excitations in this group of cells were similar, suggesting that homocysteine is at least as potent as glutamate. The excitatory effects of both homocysteine and glutamate were antagonized by local application of betaine, a biological methyl donor which blocks convulsions produced by systemic administration of pentylenetetrazol and electroshock as well as homocysteine. The effects of local application of homocysteine were also blocked by local application of the glutamate antagonist glutamate diethylester (GDEE). In 6 of 7 cells tested, GDEE appeared to preferentially affect homocysteine-induced excitations. These data indicate that homocysteine has an excitatory action on neurons, a finding which may account for some of the symptoms associated with certain disorders of amino acid metabolism.