Estimation of pA2 values at presynaptic alpha 2-autoreceptors in rabbit and rat brain cortex in the absence of autoinhibition.

An attempt was made to determine pA2 values of antagonists at the presynaptic, release-inhibiting alpha 2-autoreceptors of rabbit and rat brain cortex under conditions when there was very little released noradrenaline in the autoreceptor biophase and, hence, pA2 values were not distorted by endogenous autoinhibition. Cortex slices were preincubated with 3H-noradrenaline and then superfused and stimulated by trains of 4 pulses delivered at 100 Hz or, in a few cases, by trains of 36 pulses at 3 Hz. The alpha-adrenoceptor agonists clonidine, noradrenaline, and alpha-methylnoradrenaline concentration-dependently decreased the stimulation-evoked overflow of tritium. The alpha-adrenoceptor antagonists yohimbine, rauwolscine and idazoxan did not increase the overflow of tritium elicited by 4 pulses/100 Hz in rabbit brain slices and increased it only slightly in rat brain slices. In contrast, the antagonists increased markedly the overflow at 36 pulses/3 Hz. All antagonists caused parallel shifts to the right of the concentration-response curves of clonidine, noradrenaline, and alpha-methylnoradrenaline. pA2 values were calculated either from linear regression of log [agonist concentration ratio - 1] on log [antagonist concentration] or from sigmoid curve fitting. The slopes of the linear regression lines were close to unity, and the pA2 values calculated by the two methods agreed well. There was no consistent preferential antagonism of any antagonist to any agonist. pA2 values determined with stimulation by 4 pulses/100 Hz were by 0.53-0.80 log units higher than those determined with stimulation by 36 pulses/3 Hz.(ABSTRACT TRUNCATED AT 250 WORDS)