112 MARTIN G. LARRABEE AND PAUL HOROWICZ 



may, on the contrary, be shifts in high energy phosphate synthesis in anaero- 

 biosis, group transfer and uncoupling. It is extremely unlikely from both the 

 biological and chemical points of view that all narcotic substances, e.g., act 

 on one specific enzyme path — even if their action is primarily on intracellular 

 enzyme systems. It is well to remember that there are several enzymatic proc- 

 esses involved in the action of hypnotics, sedatives and narcotics: 



(1) Glucose to pyruvic acid (glycolytic process). 



(2) Pyruvic acid oxidized to carbon dioxide and water in the cyclophorase- 

 mitochondrial system. 



(3) Process by which acetylcholine is generated and triggers the impulse 

 (including the process of conversion of bound to free acetylcholine) 



The utilization and/or generation of energy by the system is of the first impor- 

 tance. Our results with narcotics have shown that in no case does the net 

 synthesis of ATP appear to be significantly depressed by the narcotic substances 

 in reasonable concentration. The question still remains, in vivo, of possible 

 effects on ATP utilization. Our recent results have led us to believe that there 

 is a direct relationship between A TP utilization and the activity level of the nerve 

 cells. In both rat and cat, ATP in the cortex increased markedly with anesthesia. 

 There is an increase following administration of chlorpromazine (10 mg./Kg)— 

 the amount of this increase varies in different areas and is most marked in the 

 t halamohypothalamic area. Stimulation, on the other hand, (either in the form 

 of direct electrical cortical stimulation or consequent to injection of metrazol) 

 produces a very large drop in the ATP level. 



This correlation of activity level and ATP concentration (which appears to 

 be related to the effects, for example, of certain so-called tranquilizing drugs) 

 suggests a partial explanation of some of the problems discussed this afternoon. 

 Perhaps there is a clue here to mechanisms of transport across the cell mem- 

 brane and their relation to molecular factors which enter into basic cell activity. 



Dr. McElroy: Dr. Larrabee raised several questions which were very inter- 

 esting; one, I think needs a little more clarification. That is the question on 

 what one means by different metabolic pathways, whether one means a source 

 of substrate, different types of substrate, or whether one means an entirely 

 independent metabolic mechanism other than those we already know. 



Another point is on the calculation of the ATP. I do not see how one can 

 make an argument that the energy level is not important on the basis of those 

 calculations because until you know the mechanism and extent of the electron 

 transfer through the oxidative pathway one cannot decide whether you should 

 use the P/'O ratio of three for these calculations. In other words, it could be, if 

 you want to, an alternate pathway, and this could be a non-phosphorylating 

 pathway for electron transport. One can make a calculation and say that the 

 ATP should be high, but it does not necessarily mean that it is high. 



The other thing is on the withdrawal of glucose. If you remove glucose, this 



