Four aspects of the function of histaminergic systems were studied in the rat brain: toxicology, catabolism, release in vivo, and high affinity binding of histamine. Preparations of histamine-N-methyltransferase (HNMT) derived from kidney and brain were employed in the radioenzymatic quantification of histamine in biological samples. Tritiated S-adenosyl-L-methionine ([³H]-SAM) served as the co-substrate.
A toxicological study was conducted to determine the sensitivity of the HA innervation to prenatal treatment with methylazoxymethanol (MAM), an inhibitor of mitosis. In adult rats, the MAM treatment was without effect on cerebral histamine content, although forebrain HNMT activity was 50% reduced. In another study, C-57 mice were treated with the selective dopamine neurotoxin l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Substantial dopamine depletions were not associated with alterations in the cerebral histamine content.
In a study of the structural requirements for HNMT inhibition, 9-amino-1,2,3,4-tetrahydroacridine (THA), was found to be one of the most potent inhibitors yet described. The β-carboline alkaloids, of which harmaline is the prototype, were also found to be moderately potent HNMT inhibitors. Because of the lack of high-affinity re-uptake and the absence of alternate catabolic pathways, blockade of HNMT can potentially alter central histaminergic tone. Peripheral administration of THA was able to produce dose-dependent increases in cerebral histamine content, as was the more potent HNMT inhibitor, metoprine. The issue of structural requirements for HNMT inhibition are discussed in the light of these results.
The in vivo release of histamine was studied by the cerebral microdialysis technique. After chronic implantation of horizontal probes, TTX-insensitive and partially calcium-sensitive efflux of histamine was detected in the dorsal striatum and the bed nucleus of the stria terminalis. In striatum, histamine efflux was elevated 50% after peripheral histidine loading (500 mg/kg, i.p.). After synthesis blockade with α-fluoromethylhistidine (100 mg/kg,i.p.), extracellular histamine levels in striatum disappeared in a bi-exponential manner. The half-lives of this disappearance, 32 minutes and 7 hours, indicate the presence of at least two histamine pools. Striatal histamine efflux was elevated by yohimbine treatment (10 mg/kg, i.p.), suggesting the presence of a tonic α₂-adrenergic inhibition of histamine release in vivo.
In addition to the classical H₁ and H₂ receptors, histamine is able to bind to a pharmacologically distinct site, H₃, recently characterized as an autoreceptor regulating the synthesis and release of histamine. The binding properties of the H₃ ligand [³H]-N[symbol omitted]-methylhistamine ([³H]-N-MeHA) were studied in forebrain cryostat sections by
autoradiography. Determination of Bmax (25 fmole/section) and displacement studies indicated that [³H]-N-MeHA bound to the same site as [³H]-histamine: the high affinity
histamine binding site. Binding was greatest in the basal ganglia and had a complex
distribution within the cerebral cortex. Quinolinic acid lesion studies indicated that the
majority of the binding in the basal ganglia was on striato-nigral projection neurons. Cortical
binding was also sensitive to local excitotoxic lesions. Therefore, the majority of H₃ binding
is located on postsynaptic structures intrinsic to these brain regions, rather than on presynaptic
autoreceptors on terminals of histamine neurons. / Medicine, Faculty of / Graduate
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/30687 |
| Date | January 1990 |
| Creators | Cumming, Paul Kenneth |
| Publisher | University of British Columbia |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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