Methods for the Study of Central Nervous System (CNS) Pharmacology

Methods for the Study of CNS Pharmacology

Like many areas of science, major progress in the study of CNS drugs has depended on the development of new experimental techniques. The first detailed description of synaptic transmission was made possible by the invention of glass microelectrodes, which permit intracellular recording. The development of the brain slice technique permitted an analysis of the physiology and pharmacol-ogy of synapses. Detailed electrophysiologic studies of the action of drugs on both voltage- and transmitter-operated channels were further facilitated by the introduction of the patch clamp tech-nique, which permits the recording of current through single chan-nels. Channels can be expressed in cultured cells and the currents evoked by their activation recorded (Figure 21–1). Histochemical, immunologic, and radioisotopic methods have made it possible to map the distribution of specific transmitters, their associated enzyme systems, and their receptors. Molecular cloning has had a major impact on our understanding of CNS receptors. These tech-niques make it possible to determine the precise molecular struc-ture of the receptors and their associated channels. Finally, mice with mutated genes for specific receptors or enzymes (knockout mice) can provide important information regarding the physio-logic and pharmacologic roles of these components.

Natural Toxins: Tools For Characterizing Ion Channels

Evolution is tireless in the development of natural toxins. A vast number of variations are possible with even a small num-ber of amino acids in peptides, and peptides make up only one of a broad array of toxic compounds. For example, the predatory marine snail genus Conus is estimated to include at least 500 different species. Each species kills or paralyzes its prey with a venom that contains 50–200 different peptides or proteins. Furthermore, there is little duplication of peptides among Conus species. Other animals with useful toxins include snakes, frogs, spiders, bees, wasps, and scorpions. Plant species with toxic (or therapeutic) substances are too numerous to mention here; they are referred to in many chap-ters of this book.

Since many toxins act on ion channels, they provide a wealth of chemical tools for studying the function of these channels. In fact, much of our current understanding of the properties of ion channels comes from studies utilizing only a small per-centage of the highly potent and selective toxins that are now available. The toxins typically target voltage-sensitive ion channels, but a number of very useful toxins block ionotropic neurotransmitter receptors. Table 21–1 lists some of the toxins most commonly used in research, their mode of action, and their source.