The objective of the proposed research is to elucidate the cellular mechanisms of action of a variety of drugs acting on the nervous system. It is proposed to solve the pharmacological problems by means of sophisticated physiologcal and biochemical techniques. Special emphasis is placed on the clinically important drugs which include general and local anesthetics, depressants of the central nervous sytem (antiepileptic, hypnotic, and analgesic drugs), and drugs acting on the autonomic nervous system. Neuroactive toxins and alkaloids will also be studied since they may serve as useful tools for the study of other drugs owing to their highly specific actions. The permeabilities of nerve membranes to sodium and potassium ions are the key mechanisms for excitation, and the effects of drugs are examined by means of voltage clamp and internal perfusion techniques. These parameters are taken as a measure of activity to study various aspects of the drug action, i.e. the active form of ionizable drugs and the site of action in the membrane, the mechanism of temperature dependency of drug action, and the structure-activity relation. The drug-receptor interactions are studied for long-lasting local anesthetics and tetrodotoxin by use of various techniques involving nuclear magnetic resonance, affinity chromatography, etc. These data will be integrated at a high level to interpret the mechanism of action of drugs at the membrane and molecular level.