Characterization of Histamine Release from the Rat Hypothalamus as Measured by In Vivo Microdialysis

Abstract

The release of endogenous histamine (HA) from the hypothalamus of anesthetized rats was measured by in vivo microdialysis coupled with HPLC with fluorescence detection. Freshly prepared Ringer's solution was perfused at a rate of 1 microliter/min immediately after insertion of a dialysis probe into the medial hypothalamus, and brain perfusates were collected every 30 min into microtubes containing 0.2 M perchloric acid. The basal HA output was almost constant between 30 min and 7 h after the start of perfusion, with the mean value being 7.1 pg/30 min. Thus, the extracellular HA concentration was assumed to be 7.8 nM, by a calculation from in vitro recovery through the dialysis membrane. Perfusion with a high K+ (100 mM)-containing medium increased the HA output by 170% in the presence of Ca2+. Systemic administration of either thioperamide (5 mg/kg, i.p.), a selective H3 receptor antagonist, or metoprine (10 mg/kg, i.p.), an inhibitor of HA-N-methyltransferase, caused an approximately twofold increase in the HA output 30-60 min after treatment. The combined treatment with thioperamide and metoprine produced a marked increase (650%) in the HA output. The HA output decreased by approximately 70% 4-5 h after treatment with alpha-fluoromethylhistidine (alpha-FMH; 100 mg/kg, i.p.), an inhibitor of histidine decarboxylase. Furthermore, the effect of combined treatment with thioperamide and metoprine was no longer observed in alpha-FMH-treated rats. These results suggest that both HA-N-methyltransferase and H3 autoreceptors are involved in maintaining a constant level of extracellular HA and that their blockade effectively results in a higher activity level of the endogenous histaminergic system in the CNS.

Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight

“…This original finding is interesting from the point of view that it has previously been demonstrated that the PVN plays a central role in the histaminergic regulation of food intake 21 and that it harbours a population of H 1 and H 3 receptors. 22 This finding adds further support to the view that the histamine H 3 receptor is essential for regulating the histamine release and synaptic histamine concentration, 15,16,[23][24][25] and that this concentration can be increased Neural histamine and food intake K Malmlöf et al as thioperamide 26,27 are associated with an acute decrease of food intake. In one study performed by Attoube et al, 28 these findings were reproduced also after peripheral administration of the same drug.…”

Discovery of Histamine H3 Antagonists for the Treatment of Cognitive Disorders and Alzheimer's Disease

“…The initial characterization of H 3 autoreceptors used histamine release from brain slices, and the first report of H 3 antagonist-evoked histamine release in the whole animal was demonstrated in the hypothalamus of thioperamidetreated rats (Itoh et al, 1991;Mochizuki et al, 1991 receptor antagonism produced by systemic administration of 5-cyclohexyl-1-(4-imidazol-4-ylpiperidyl)pentan-1-one (GT-2016) increased histamine in the parietal cortex of awake, freely moving rats (Tedford et al, 1995). In addition, several selective H 3 antagonist have been shown to increase extracellular histamine levels in the rat prefrontal cortex, the TMN, and the basolateral amygdala after systemic thioperamide administration (Cenni et al, 2004).…”

BF2.649 [1-{3-[3-(4-Chlorophenyl)propoxy]propyl}piperidine, Hydrochloride], a Nonimidazole Inverse Agonist/Antagonist at the Human Histamine H3 Receptor: Preclinical Pharmacology

“…In contrast, presynaptic H 3 receptors are almost exclusively expressed in the central nervous system, and their blockade by drugs such as thioperamide markedly enhances the activity of histaminergic neurons, as shown namely by the increases in histamine (HA) release and turnover in rodent brain (Arrang et al, 1987;Garbarg et al, 1989;Itoh et al, 1991;Mochizuki et al, 1991). The use of this prototypical autoreceptor antagonist in numerous studies to enhance brain HA release has been instrumental in establishing the roles of tuberomammillary neurons in behavior (for review, see Onodera et al, 1994;Hill et al, 1997;Brown et al, 2001).…”