The present study explores pharmacologically on the model spontaneously beating 3H-noradrenaline pretreated guinea-pig atrial preparation the mechanism(s) by which the representative central nervous system (CNS) stimulant drug 3-methyl-3-ethylglutarimide (bemegride, MEG) and its representative CNS depressant homologue 3-methyl-3-n-butylglutarimide (MBG) affect transmitter release and the force and rate of atrial contraction and contracture, as well as the relevance of these atrial mechanism(s) to those involved in the production of drug-evoked convulsions and hypnosis in the mammalian CNS. The process(es) involved in the interaction of MEG and MBG on the atrial preparation have also been studied to provide insight into possible CNS mechanism(s) that may be involved in the related central phenomena of drug-induced analepsis and anticonvulsant action. It would appear that the actions and interactions of MEG and MBG on the atrium and in the mouse both depend critically on glutarimide-evoked enhancement (MEG) or inhibition (MBG) of Ca2+ flux through potential-operated Ca2+ channels located primarily on the responsive atrial sarcolemmal and neuronal synaptic membranes, respectively. In addition, it seems likely that the reciprocal antagonism shown by these substances on the atrium and in the CNS is predominantly functional in nature. The pharmacological and clinical implications of these findings are discussed, with particular reference to the possible benefit of selective calcium antagonists and related drugs in the management of drug dependence and withdrawal.