Subtype-specificity of the presynaptic alpha 2-adrenoceptors modulating hippocampal norepinephrine release in rat.
In vivo brain microdialysis and high-performance liquid chromatography with electrochemical detection were used to study the effect of different selective alpha 2-antagonists on hippocampal norepinephrine (NE) release in freely moving awake rat. Systemic administration (0.5 mg/kg i.p.) of either the alpha 2AD-antagonist BRL 44408 or the alpha 2BC-antagonist ARC 239 did not significantly change the basal release of NE. At a higher dose (5 mg/kg i.p.) ARC 239 was still ineffective, whereas BRL 4408 caused a significant increase of the extracellular level of NF. Similar results were obtained from in vitro perfusion experiments. Rat hippocampal slices were loaded with [3H]NE and the electrical stimulation-evoked release of [3H]NE was determined. The alpha 2-antagonists were applied in a concentration range of 10(-8) to 10(-6) M, ARC 239 was ineffective, whereas BRL 44408 significantly increased the electrically induced release of [3H]NE. In agreement with the data of microdialysis and perfusion experiments, BRL 44408 displaced [3H]yohimbine from hippocampal and cortical membranes of rat brain with high affinity whereas ARC 239 was less effective. The pKi values of eight different alpha 2-adrenergic compounds showed a very good correlation (r = 0.98, slope = 1.11 P < 0.0001) in hippocampus and frontal cortex have the alpha 2-adrenoceptors have been characterized as alpha 2d-subtype. Our data indicate that hippocampal NE release in rat is regulated by alpha 2D-adrenoceptors, a species variation of the human alpha 2A-subtype.
Kiss
J P
JP
Department of Pharmacology, Institute of Experimental Medicine, Hunagarian Academy of Sciences, Budapest.
Zsilla
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G
Mike
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A
Zelles
T
T
Toth
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E
Lajtha
A
A
Vizi
E S
ES
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D006624:Hippocampus / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000378:metabolism; D017551:Microdialysis; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000378:metabolism*; D015016:Yohimbine / Q000378:metabolism
D018341:Receptors, Adrenergic, alpha-2; D017661:Receptors, Presynaptic; D015016:Yohimbine; D009638:Norepinephrine