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

We hypothesized that divalproex sodium, an anticonvulsant effective in the acute treatment of mania, may act upon neuropeptide systems that utilize co rticotropin-releasing factor (CRF). Pharmacokinetic studies demonstrated th at valproate has an apparent elimination half life of 17 minutes in rats af ter acute administration and that there is a nonlinear relationship between chronic dose and serum drug concentration. Acute valproate treatment neith er altered plasma adrenocorticotropic hormone (ACTH) or corticosterone conc entrations nor produced changes in CRF concentration in any of 10 brain reg ions 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 modula tor of GABAergic function, similarly decreases CRF mRNA expression in the C eA. These results suggest that the mood stabilizing effects of valproic aci d may be mediated in part by alterations in CRF neuronal activity. (C) 2001 American College of Neuropsychopharmacology. Published by Elsevier Science Inc.