Chronic high-dose glycine nutrition: effects on rat brain cell morphology

Background: Facilitation of N-methyl- -aspartate (NMDA) receptor–mediated neurotransmission via administration of glycine site agonists of the NMDA receptor (e.g., glycine, -serine), and glycine transport inhibitors may represent an innovative pharmacologic strategy in schizophrenia; however, given the potential involvement of NMDA receptors in the neurotoxicity of excitatory amino acids, possible neurotoxic effects of glycinergic compounds need to be explored. Furthermore, studying brain adaptations to chronic administration of glycine site agonists may provide insights into the therapeutic mechanisms of these drugs. Methods: Adult rats were randomized to one of three nutritional regimens (no glycine supplementation, 1 g/kg/day, or 5 g/kg/day glycine supplementation) and to one of three treatment durations (1, 3, or 5 months). Serum glycine and serine levels at sacrifice and brain sections were examined using histologic markers of neurodegeneration (cresyl violet and silver impregnation staining) and immunohistochemical staining of glial fibrillary acidic protein, microtubule-associated protein, and neurofilament 200. To explore additional neural adaptations to high-dose glycine treatment, immunostaining was also performed for class B, N-type Ca2+ channels. Results: Serum glycine levels increased dose dependently during glycine nutrition, whereas serine levels were not changed. In hippocampal dentate gyrus, the percentage of hypertrophied astrocytes transiently increased at 1 month. At 3 and 5 months of glycine treatment, the density of class B, N-type Ca2+ channels was reduced in parietal cortex and hippocampus. No evidence of neuronal or glial cell excitotoxic damage or degeneration was registered at either of the treatment intervals studied. Conclusions: These findings demonstrate for the first time that in vivo administration of high-dose glycine may induce brain morphological changes without causing neurotoxic effects. A reduction in density of class B, N-type Ca2+ channels in specific brain regions may represent one general adaptation to long-term, high-dose glycine treatment.