Endogenous GABA Modulates Histamine Release from the Anterior Hypothalamus of the Rat

Abstract

Using a microdialysis method, we investigated the effects of the nipecotic acid-induced increase in content of endogenous GABA on in vivo release of histamine from the anterior hypothalamus (AHy) of urethane-anesthetized rats. Nipecotic acid (0.5 mM), an inhibitor of GABA uptake, decreased histamine release to -~60%of the basal level. This effect was partially antagonized by picrotoxin (0.1 mM), an antagonist of GABAA receptors, or phaclofen (0.1 mM), an antagonist of GABAB receptors. These results suggest that histamine release is modulated by endogenous GABA through both GABAA and GABAB receptors. When the tuberomammillary nucleus, where the cell bodies of the histaminergic neurons are localized, was stimulated electrically, the evoked release of histamine from the nerve terminals in the AHy was significantly enhanced by phaclofen, suggesting that GABAB receptors may be located on the histaminergic nerve terminals and modulate histamine release presynaptically. On the other hand, picrotoxin caused an increase in histamine release to~-~1 70% of the basal level, and this increase was diminished by coinfusion with -) -2-amino-5-phosphonopentanoic acid (0.1 mM), an antagonist of NMDA receptors. Previously, we demonstrated tonic control of histamine release by glutamate mediated through NMDA receptors located on the histaminergic terminals in the AHy. These results suggest the possible localization of GABAA receptors on glutamatergic nerve terminals and that the receptors may regulate the basal release of histamine indirectly.

Glutamatergic regulation of brain histamine neurons: In vivo microdialysis and electrophysiology studies in the rat

“…Blockade of NMDA receptors of this sub-population results in enhanced histaminergic activity. Thus, microdialysis experiments showed that systemic administration of NMDA antagonists resulted in an increased release of histamine (Fell et al, 2010;Okakura-Mochizuki et al, 1996). Increased telemethylhistamine levels as well as enhanced histidine decarboxylase mRNA expression were seen after systemic administration of NMDA antagonists (Faucard et al, 2006).…”

“…Separately, both neurotransmitter systems are well documented. Although less widely studied, evidence exists that there is a functional interaction between the glutamatergic and the histaminergic systems (Fell et al, 2010;Okakura-Mochizuki et al, 1996).…”

The wake-promoting transmitter histamine preferentially enhances alpha-4 subunit-containing GABAA receptors

“…Although histamine operates through a family of G-protein coupled receptors(Haas et al, 2008), it has also been shown to act through allosteric sites on two structurally unrelated ionotropic receptors, the NMDA glutamate receptor(Bekkers, 1993; Vorobjev et al, 1993) and GABA A receptor channels(Saras et al, 2008). Although there is no current evidence for co-release of GABA and histamine, GABA is co-synthesized in the histamine neurons of the tuberomamillary nucleus(Airaksinen et al, 1992; Haas et al, 2008), and GABA modulates histamine release(Okakura-Mochizuki et al, 1996). Histamine has autocrine action on TMN neurons via H3 auto-receptors(Haas and Panula, 2003), raising the possibility of spillover influencing other targets such as GABA A receptors, which are also expressed in the TMN neurons.…”

Neuropharmacology of Histamine in Brain

“…Histamine turnover in the brain is also rapidly reduced after administration of GABAergic sedative drugs such as barbiturates and benzodiazepines [398,416], presumably as a result of their interaction with GABA A receptors present on histaminergic neurons [369]. In vivo microdialysis shows that endogenous GABA as well as systemic administration of muscimol, pentobarbital, diazepam, and halothane inhibits histamine release in the rat brain [417][418][419]. GABA A receptors present in the tuberomammillary nucleus play a key role in the sedative component of anesthesia.…”