Dehydration associated with hyperosmolality and decreased extracellular volume stimulates arginine vasopressin (AVP) and oxytocin (OT) secretion from magnocellular neurons of the hypothalamus. The effects of hyperosmolality and decreased extracellular volume on the magnocellular neurons are mainly indirect and seem to be mediated centrally via several neurotransmitters and neuropeptides. Because histamine (HA), which serves as a central neurotransmitter, releases AVP and OT from the neurohypophysis when administered centrally, we investigated the possible role of HA in dehydration-induced AVP and OT secretion. To do this, we studied 1) the effect of dehydration on messenger RNA (mRNA) expression of the HA synthesis enzyme, histidine decarboxylase (HDC), in the tuberomammillary nucleus of the hypothalamus; and 2) the effect of HA synthesis inhibition during dehydration on AVP and OT mRNA expression in the supraoptic nucleus of the hypothalamus as well as on plasma AVP and OT levels. Forty-eight hours of dehydration increased the mRNA level of HDC in the tuberomammillary nuclei, whereas 24 h of dehydration had no effect. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha FMH) increased the expression of HDC mRNA in 24-h dehydrated rats, but had no effect in euhydrated rats. In rats dehydrated for 48 h, the already increased level of HDC mRNA was not increased further by alpha FMH. Twenty-four and 48 h of dehydration increased AVP and OT mRNA levels in the supraoptic nucleus. This effect was inhibited by alpha FMH pretreatment. Dehydration increased the plasma levels of AVP and OT to an extent which depended on the duration of dehydration. Pretreatment with alpha FMH inhibited the hormone responses to 24 h of dehydration, but did not affect the responses to 48 h of dehydration. Twenty-four and 48 h of dehydration had no significant effect on the contents of AVP and OT in the neurohypophysis, whereas pretreatment with alpha FMH combined with 48 h of dehydration led to depletion of AVP stores in the neurohypophysis. Based on the present findings, we conclude that hypothalamic histaminergic neurons are involved in the regulation of dehydration-induced stimulation of magnocellular AVP and OT neurons.