Characterization of the alpha(2)-adrenoceptor subtype, which functions as alpha(2)-autoreceptor in human neocortex

The pharmacological properties of the alpha(2)-adrenergic receptors regulating the release of norepinephrine were investigated in human neocortex. Slices were preincubated with [(3)H]norepinephrine, superfused under blockade of transmitter reuptake, and stimulated electrically. First, the autoinhibitory circuit of [(3)H]norepinephrine release was analyzed quantitatively by estimation of the K(d) of norepinephrine at the alpha(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 pEC(50) 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 alpha(2A) binding sites. In contrast, the correlations with alpha(2B), alpha(2C), and alpha(2D) sites were not as good. It is concluded that in human neocortex prejunctional autoreceptors are alpha(2A).