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

Neuroscience. 1999;91(1):211-9. doi: 10.1016/s0306-4522(98)00615-0.


The production and release of the corticosteroids, namely the glucocorticoids and the mineralocorticoids, are regulated by various stimuli, including stress. Previous studies from our laboratory have shown that chronic exposure 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 phenytoin, which suppresses glutamate release, and also by N-methyl-D-aspartate receptor antagonists. These results suggest an interaction between glucocorticoids and excitatory amino acids in the development of stress-induced atrophy of CA3 pyramidal neurons. Since nitric oxide is proposed to play an important role in mediating both the physiological and pathophysiological actions 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 messenger RNA in hippocampal pyramidal neurons and granule neurons of the dentate 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-administration led to a significant reduction in neuronal nitric oxide synthase messenger RNA levels when compared with vehicle controls. These results suggest that, during exposure to stress levels of corticosterone, phenytoin inhibits glucocorticoid-induced atrophy of CA3 pyramidal neurons by reducing neuronal nitric oxide synthase expression in hippocampal interneurons. Moreover, these results may provide another example of synaptic plasticity in the hippocampus mediated by nitric oxide synthase.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Anticonvulsants / pharmacology*
  • Autoradiography
  • Corticosterone / pharmacology*
  • Hippocampus / drug effects
  • Hippocampus / enzymology*
  • In Situ Hybridization
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Male
  • Neurons / drug effects
  • Neurons / enzymology*
  • Nitric Oxide Synthase / biosynthesis*
  • Nitric Oxide Synthase Type I
  • Phenytoin / pharmacology*
  • Pyramidal Cells / drug effects
  • Pyramidal Cells / metabolism
  • RNA Probes
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley


  • Anti-Inflammatory Agents
  • Anticonvulsants
  • RNA Probes
  • RNA, Messenger
  • Phenytoin
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type I
  • Nos1 protein, rat
  • Corticosterone