neurophysiology: an integration 



i9'-'9 



inhibit enzymes, disperse or gel colloids, alter folding 

 and linkage of macromolecules, and in general initiate 

 the complex of chemical, structural and dynamic 

 changes that constitute physiological action (84). 

 The close reciprocal influence of membrane con- 

 ductance and of ion flow and concentration, each 

 highly sensitive to the other (141; Eccles; Tasaki), is 

 probably the secret of conductile tissue. Indeed, the 

 physicochemical interaction between free and struc- 

 turally fixed ions may control a great variety of bio- 

 logical phenomena (182; Ling, manuscript in prep- 

 aration). 



The amounts can be altered by diet or by excretion 

 or other removal (as citrate binding calcium ), but 

 mainly by changes in the rate of production or de- 

 struction within the cell or body. If enzyme 1 catalyzes 

 molecule A to molecule B, and enzyme 2, B to C, 

 then inactivation of 1 will increase A and decrease 

 B, and lack of 2, increase B and decrease ( 1. Whether 

 B increases or decreases, its final effect on function 

 could be the same. An increase in B might block some 

 other enzyme and so lead to a deficit in D; but B 

 might, conversely, catalvze D production, in which 

 case a decrease in B would lead 10 a deficit in I). An 

 increase in D could, of course, equally follow a change 

 in B. 



It seems a reasonable guess that, in the course ol 

 evolution, each cell or cell region has evolved a pat- 

 tern of chemical architecture and traffic How thai is 

 essentially optimal to its functions so thai imbalance 

 of any important component, either up or down, 

 might be disturbing. Nevertheless, deficiencies of 

 naturally occurring molecules seem more disrupting 

 than do excesses of them, perhaps because more easy 

 corrections are available for an excess, and the ulti- 

 mate etlects of damage are ,1 slowing down rather than 

 a speeding up of metabolism. Probably some deficit 

 in molecules used for structures or lor energy is die 

 final bottleneck that prevents normal functioning; 

 but deficits in molecules involved directly in function 

 are more immediate ( 1 1 1 I. 



When a substance is effective on the nervous swem 

 in minute doses, it is reasonably certain that it is 

 acting on specific molecules and even at limited loci; 

 when only large concentrations are effective, some 

 general physical action, as one involving lipoid solu- 

 bility, is more probable. Half a gram of pentylene- 

 tetrazol is required to produce convulsions in man; 

 one tenth of a milligram of strychnine does so. Grams 

 of alcohol or ether are required for their effects, but 

 0.2 mg of LSD produces hallucinations and 0.25 

 gamma of botulinus toxin can lead to fatal paralysis. 



It will help progress and limit theorizing if more 

 attention is given to the concentrations at which sub- 

 stances produce their influences on the nervous system. 



Neglect of differences between cells, and between 

 cell regions, has also led to much confusion. It is 

 doubtful if, today, we have quantitatively meaning- 

 ful information on the amount of any substance in anv 

 functionally significant locus in any cell in the nervous 

 system (but see Abood). The same is even more true 

 regarding rates of production and destruction, of re- 

 lease from a 'bound' form or from an impermeable 

 compartment and of removal In- diffusion or circula- 

 tion, of precursor storage and movement or of kinase 

 activation and availability, and of like data which are 

 essential to rationalization and prediction at the 

 chemical-physiological, or molecular-organdie, level. 

 Nonetheless considerable qualitative understanding 

 has developed leg. Richter (24'^j, perhaps best ex- 

 hibited in relation lo chemical pathology. 



Pathology. Specific lacks ol some kind underlie the 

 inborn metabolic disc.iscs ol the nervous s\s|em (both 

 such clear cases as oligophrenia phenylpv ruvica and 

 Hartnup's disease and such less clear or debated ones 

 as Wilson's disease or schizophrenia), dietary defi- 

 ciency diseases (Brozek & Grande), and main actions 

 of drugs and poisons. It b\ no means follows thai such 

 situations are impossible or even difficult to neat. 

 (Interestingly, niacin may relieve amnesia and hallu- 

 cinations of pellagra, while neural lesions progress 

 downhill, according to Brozek & Grande. ) The missing 

 substance may be supplied, a destroyed enzyme sup- 

 plemented (permeability problems make this mote 

 difficult but, again, by no means impossible), or diets 

 adjusted to eliminate a nonmetabolized substance; 

 and various ones of these measures can be and have 

 been Used. Consider three examples. 



A type of feeble-mindedness associated with the 

 presence of phenvlpvruvic acid in the urine was 

 identified in the mid-thirties. During a couple of 

 decides this inborn metabolic disorder of the nervous 

 swem has been thoroughly analyzed and brought 

 at least partly under control (74). The phenvlpvruvic 

 acid excess is lormed from an excess of phenylalanine, 

 an essential dietary amino acid, the normal metabolic 

 path of which, an oxidation to tyrosine, is closed. 

 From tyrosine any number of catechol amines which 

 normally form might be deficient; conversely, excess 

 phenylalanine metabolites have been shown by 

 Bessman & Tada (23) to interfere with the metabolism 

 of indole compounds. All components of the reaction 

 are present except a specific enzyme in the fixer, so 

 this particular disease of the nervous system turns out 



