THE SLOPE PARAMETER OF CONCENTRATION-RESPONSE CURVES USED AS A TOUCHSTONE FOR THE EXISTENCE OF SPARE RECEPTORS

The present work was stimulated by findings of a large reserve of pres ynaptic alpha(2)-autoreceptors in rat neocortex by different investiga tors and our own group, using classical models of receptor agonism. Th e mathematical background of these classical models seems erroneous si nce the asymmetry that spare receptors introduce into concentration-re sponse curves is not considered appropriately. This asymmetry leads to a steepening of curve fits based on the logistic function. Therefore, the slope parameter c of a logistically fitted concentration-response curve can be used as a touchstone for the existence of spare receptor s. Spare receptors induce a c > 1. Concentration-response data of the alpha(2)-autoreceptor-mediated inhibition of evoked [H-3]-noradrenalin e release in rat neocortex slices were re-analysed. The estimates of t he slope parameter c of logistically fitted concentration-response cur ves obtained after treatment of rats with either vehicle or N-ethoxyca rbonyl-2-ethoxy-1-2-dihydroquinoline (EEDQ) to achieve an irreversible inactivation of alpha(2)-autoreceptors, were not compatible with the existence of a large receptor reserve. A model for nonlinear regressio n analysis developed under the a priori assumption of spare receptors confirmed the absence of spare receptors. Evaluation methods which neg lect the alteration of the geometrical form of concentration-response curves due to non-proportionality between receptor occupation and rela tive response do not seem appropriate to quantify spare receptors. The se methods may detect spare receptors where they do not exist.