Abstract
The pharmacological properties of the α2-adrenergic receptors regulating the release of norepinephrine were investigated in human neocortex. Slices were preincubated with [3H]norepinephrine, superfused under blockade of transmitter reuptake, and stimulated electrically. First, the autoinhibitory circuit of [3H]norepinephrine release was analyzed quantitatively by estimation of theKd of norepinephrine at the α2-autoreceptor (10−7.99 M), the concentration of the endogenous transmitter causing this autoinhibition at a stimulation frequency of 3 Hz (10−7.61 M), and the maximum inhibition obtainable through the autoreceptor (83%). Second, antagonist pKb values of nine antagonists were determined by using their pEC50 values (negative logarithms of antagonist concentrations that increased the electrically evoked overflow of tritium by 50%) against the release-inhibiting effect of the endogenous transmitter. When compared with binding or functional data from the literature, the pKbvalues correlated best with the antagonist affinities at α2A binding sites. In contrast, the correlations with α2B, α2C, and α2D sites were not as good. It is concluded that in human neocortex prejunctional autoreceptors are α2A.
Footnotes
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Send reprint requests to: Dr. T. J. Feuerstein, Sektion Klinische Neuropharmakologie der Neurologischen Universitätsklinik, Breisacherstrasse 64, D-79106 Freiburg, Germany. E-mail:feuer{at}ukl.uni-freiburg.de
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↵1 This work was supported by the Deutsche Forschungsgemeinschaft (SFB 505, TP C4, C8).
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↵2 Present address: Neurochirurgische Universitätsklinik, Breisacherstrasse 64, D-79106 Freiburg, Germany.
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↵3 Present address: Pharmakologisches Institut der Universität Freiburg, Hermann-Herder-Strasse 5, D-79104 Freiburg, Germany.
- Abbreviations:
- ARC 239
- 2-{2-[4-(o-methoxyphenyl)piperazin-1-yl]ethyl}-4,4-dimethyl-1,3(2H,4H)-isoquinolinedione
- WB4101
- (±)-2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane HCl
- SKF104078
- 6-chloro-9-((3-methyl-2-butenyl)oxy)-3-methyl-1H-2,3,4,5-tetrahydro-3-benzazepine maleate
- CI95
- 95% confidence interval
- Received November 30, 1999.
- Accepted April 4, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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