A ROLE FOR COMPUTER-SIMULATION IN SOLVING THE RIDDLES OF AUTORECEPTOR-MEDIATED REGULATION OF GABA RELEASE

The autoreceptor-mediated control of GABA release was simulated on a p ersonal computer using commercially available software (STELLA(TM)/ITH INK(TM)). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce f requency dependencies of GABA release in the presence and absence of u ptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (-)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious m ismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indica te a 3-fold increase in release as compared to controls, simulation pr edicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the aut oreceptor occurring as two subtypes with different affinities for anta gonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentration s of endogenous GABA, and (c) overruling of uptake inhibition by marke dly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a r estricted replacement capacity for exocytotically emptied synaptic ves icles at their docking sites gave similar results. As a consequence, w e shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help t o exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found s imulation with this user-friendly software extraordinarily useful, als o and not least because it necessitates and stimulates very intense de aling with a subject.