Corticosterone and phenytoin reduce neuronal nitric oxide synthase messenger: RNA expression in rat hippocampus

The production and release of the corticosteroids, namely the glucocorticoi ds and the mineralocorticoids, are regulated by various stimuli, including stress. Previous studies from our laboratory have shown that chronic exposu re to stress or to stress levels of glucocorticoids produces atrophy of the apical dendrites of CA3 pyramidal neurons in the hippocampus. This stress- induced dendritic remodeling is blocked by the anti-epileptic drug phenytoi n, which suppresses glutamate release, and also by N-methyl-D-aspartate rec eptor antagonists. These results suggest an interaction between glucocortic oids and excitatory amino acids in the development of stress-induced atroph y of CA3 pyramidal neurons. Since nitric oxide is proposed to play an impor tant role in mediating both the physiological and pathophysiological action s of excitatory amino acids, we examined the regulation of neuronal nitric oxide synthase messenger RNA expression by corticosterone and phenytoin in the rat hippocampus. The expression of neuronal nitric oxide synthase messe nger RNA in hippocampal pyramidal neurons and granule neurons of the dentat e gyrus was unaffected by 21-day administration of corticosterone (40 mg/kg ), phenytoin (40 mg/kg) or the combination of corticosterone and phenytoin. However, in hippocampal interneurons, corticosterone/ phenytoin co-adminis tration led to a significant reduction in neuronal nitric oxide synthase me ssenger RNA levels when compared with vehicle controls. These results suggest that, during exposure to stress levels of corticoster one, phenytoin inhibits glucocorticoid-induced atrophy of CA3 pyramidal neu rons by reducing neuronal nitric oxide synthase expression in hippocampal i nterneurons. Moreover, these results may provide another example of synapti c plasticity in the hippocampus mediated by nitric oxide synthase. (C) 1999 IBRO, Published by Elsevier Science Ltd.