Effects of sodium valproate on corticotropin-releasing factor systems in rat brain

Neuropsychopharmacology. 2001 Jun;24(6):624-31. doi: 10.1016/S0893-133X(00)00243-8.


We hypothesized that divalproex sodium, an anticonvulsant effective in the acute treatment of mania, may act upon neuropeptide systems that utilize corticotropin-releasing factor (CRF). Pharmacokinetic studies demonstrated that valproate has an apparent elimination half life of 17 minutes in rats after acute administration and that there is a nonlinear relationship between chronic dose and serum drug concentration. Acute valproate treatment neither altered plasma adrenocorticotropic hormone (ACTH) or corticosterone concentrations nor produced changes in CRF concentration in any of 10 brain regions examined. Subchronic treatment via SC-implanted osmotic minipumps (875 mg/kg/day x 7 days) resulted in decreased CRF concentrations in the median eminence and raphe nuclei. Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus. The benzodiazepine alprazolam, also a positive modulator of GABAergic function, similarly decreases CRF mRNA expression in the CeA. These results suggest that the mood stabilizing effects of valproic acid may be mediated in part by alterations in CRF neuronal activity.

Publication types

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

MeSH terms

  • Animals
  • Anticonvulsants / pharmacokinetics*
  • Corticosterone / metabolism
  • Corticotropin-Releasing Hormone / drug effects*
  • Corticotropin-Releasing Hormone / metabolism
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Hypothalamo-Hypophyseal System / drug effects*
  • Hypothalamo-Hypophyseal System / metabolism
  • Male
  • Neurons / drug effects*
  • Neurons / metabolism
  • Pituitary-Adrenal System / drug effects
  • Pituitary-Adrenal System / metabolism
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Synapses / drug effects
  • Synapses / metabolism
  • Valproic Acid / pharmacokinetics*


  • Anticonvulsants
  • RNA, Messenger
  • Receptors, Corticotropin-Releasing Hormone
  • CRF receptor type 1
  • Valproic Acid
  • Corticotropin-Releasing Hormone
  • Corticosterone