CENTRAL NERVOUS SYSTEM METABOLISM IN VITRO 



l8 39 



response in oxygen uptake and lactic acid production 

 of electrically excited cerebral tissue slices but had no 

 effect upon unstimulated tissue nor on tissue treated 

 with potassium salts or 2,4-dinitrophenol (127). 

 Lysergic acid diethylamide, mescaline and ergotoxin 

 similarly affected stimulated metabolism at concen- 

 trations ineffective upon unstimulated respiration 

 (114). Other agents affecting cerebral metabolism m 

 vitro include snake venoms, the neurochemical effects 

 of which have been discussed by Braganca (18). 



The very considerable literature concerning thera- 

 peutic agents and cerebral metabolism has been dis- 

 cussed elsewhere (81, 83, 136). Brief comment here 

 is confined to a few depressants and anticonvulsants 

 as examples of the biochemical problems encountered 

 in investigating centrally acting drugs. In vitro studies 

 have been carried out largely in systems with intact 

 cells and only a few in systems in which the cells 

 have been broken down. 



Recent work with electrically stimulated nervous 

 tissue has indicated ways in which depressants 

 in vivo decreased respiration and lactic acid produc- 

 tion, and increased levels of creatine phosphate. With 

 cerebral tissue slices, in which the metabolism was 

 increased by electrical pulses, potassium salts and 

 2,4-dinitrophenol, it was shown (131) that depress- 

 ants such as phenobarbital, butabarbital and chloral 

 at io -4 m decreased the stimulated respiration 

 markedly and the stimulated lactic-acid production 

 slightly, while having no effect upon unstimulated 

 metabolism. Anticonvulsants have similarly been 

 examined (54, 67), and interesting differences noted 

 between them and depressants. Thus trimethadione 

 at io -2 M had no effect upon respiration stimulated 

 by low-frequency condenser pulses, but at to -8 M 

 suppressed respiration stimulated by high frequency 

 sine-wave pulses. A general depressant such as 

 butabarbital depressed the respiration stimulated by 

 both types of pulses. The increased lactate formation 



was generally less susceptible to the action of these 

 agents than was oxygen uptake. Bromide, the in vivo 

 effects of which are related to chloride concentration, 

 has been examined in vitro in a chloride-free medium 

 (208). Concentrations up to 50 mM did not effect cere- 

 bral tissues as regards response to condenser pulses or 

 to stimulation with potassium nitrate. However, like 

 trimethadione, bromide at 2 X io -2 M inhibited 

 respiration increased by high frequency pulses (54). 

 In the superior cervical ganglion of the rabbit it 

 has been established that clinically effective concen- 

 trations of depressants block synaptic transmission 

 and also diminish the increased oxygen uptake re- 

 sulting from applied electrical pulses, although 

 having no effect upon the resting oxygen uptake 

 (107). These findings, together with those described 

 above for cerebral tissue slices, make it probable 

 that depressants and anticonvulsants primarily 

 inhibit energy-consuming processes and that the 

 metabolic changes found in vivo are in consequence 

 of such inhibition. 



Concentrations of general depressants higher than 

 those effective clinically (123) depress the unstimu- 

 lated oxygen uptake and the lev eh of creatine phos- 

 phate of cerebral slues j|, ; ;, u8, [36, I-)I, 203 



and numerous studies have sought to establish their 

 action in terms of inhibition of metabolic |>n < esses. 

 Concentrations of to ' m ' \t decrease both oxygen 

 uptake and laetie acid production in homogenates 

 (68, 166, 203), and also the rate of formation of 

 adenosine triphosphate (25, 39, 86, 87). Similarly 

 concentrations of from 4 to 30 times those effective 

 in vivo have been described .is •uncoupling' oxidative 

 phosphorylation in cerebral mitochondrial prepara- 

 tions in, jo j ;i. Interference with enzymes directly 

 involved in creatine phosphate and adenosine tri- 

 phosphate metabolism has not been observed (66, 

 '57)- 



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