Haloperidol, a D2 dopamine receptor blocking drug, exerts therapeutic actions in Tourette Syndrome, but also. has undesirable side-effects. Although the binding of haloperidol and related drugs to the dopamine receptor has been extensively studied, relatively little is known about drugs which might block the membrane ion channels through which the receptor gives rise to a change in neuronal activity. There is some evidence that the D2 receptor may work through more than one kind of ion channel. Therefore, there is a possibility that drugs which block just one channel might have some, but not all, of the pharmacologic actions of haloperidol. The goal of this study is to clarify the identity of dopamine-modulated ion channels, and to characterize some of the compounds which may be able to block these channels. Experiments will be performed on neurons dissociated from the corpus striatum region of rat brain. Patch-clamp electrophysiology will be used to measure the electrical current passing through ion channels. This new technique involves sealing a polished glass microelectrode to the surface of the cells, and permits resolving the current passing through a single molecule of ion channel. An 85 pS potassium channel activated by D2 receptors has already been studied. Studies will now center on whether channels differ among various cell types in the striatum, and will examine the ability of a number of compounds to selectively block current through these channels. Preliminary studies have already found that some compounds containing a quinuclidinyl chemical group are very potent blockers. An understanding of channel blockade at the basic science level is a necessary first step in the rational development of potential new therapeutic drugs. Jonathan E. Freedman, Ph.D. Northeastern University College of Pharmacy, Boston, MA Award $25,000 Tourette Association of America Inc. – Research Grant Award 1990