Vol. 294, Issue 1, 356-362, July 2000

Characterization of the ₂-Adrenoceptor Subtype, Which Functions as ₂-Autoreceptor in Human Neocortex¹

Thomas J. Feuerstein, Boris Huber, Jan Vetter, Heike Aranda, Vera Van Velthoven² and Norbert Limberger³

Sektion Klinische Neuropharmakologie der Neurologischen Universitätsklinik, Freiburg, Germany

The pharmacological properties of the ₂-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 the K_d of norepinephrine at the ₂-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 pK_b 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 pK_b values correlated best with the antagonist affinities at _2A binding sites. In contrast, the correlations with _2B, _2C, and _2D sites were not as good. It is concluded that in human neocortex prejunctional autoreceptors are _2A.