In an attempt to clarify the nature of histaminergic neuromodulation of the vasopressinergic system, several studies under different experimental paradigms were carried out. L-Histidine loads (8 mmol/kg, i.p.) induced a marked increase in histamine (HA) in the anterior (AHR) and posterior (PHR) hypothalamic regions, the median eminence (ME) and adenohypophysis (Ah) with no apparent effect on the concentration of HA in the neurohypophysis (Nh), as measured by high-performance liquid chromatography. These findings correlated with decreases in vasopressin (VP) levels in the AHR and ME, accompanied by increases of the neuropeptide in the PHR and Ah. Intraperitoneal injections of HA (6 µmol/kg), resulted in a significant (p < 0.005) rise in VP levels in the PHR, ME and Ah. HA induced an elevation of VP in the prefrontal cortex (PFC) from 6.23 ± 2.02 to 43 ± 4.05 µU/mg, as well as a 60% reduction in neurohypophyseal VP. These HA-induced VP responses were abolished by both mepyramine (3 µmol/kg) and famotidine (4 µmol/kg) in the PHR and PFC. Mepyramine suppressed the HA-induced VP response in the Ah and enhanced it in the Nh, while famotidine did the opposite. When alpha-fluoromethylhistidine (FMH), an irreversible inhibitor of histidine decarboxylase, was administered at doses of 100 mg/kg/day (i.p.), hypothalamic HA levels fell by 40–45% after 1 h, by 50% after 3 h, and by 65–80% after 24 h in adrenalectomized rats. In the same conditions, but after a week of treatment with FMH, the VP response to adrenalectomy was clearly impaired. These results seem to demonstrate that the physiological levels of neuronal HA are indispensable for the normal functioning of the neuroendocrine system. In this context, preliminary pharmacological evidence showed that histaminergic neuromodulation of the vasopressinergic system is mediated through H1 receptors in the Ah, H1 receptors in the ME and Nh, and both H1 and H2 receptors in the PFC and hyp