CEREBRAL PASSAGE OF FREE AMINO ACIDS 559 
It has to be emphasized that the finding of a decrease in the cerebral level when 
the plasma level was above that of the brain can have, in addition to active transport, 
these alternate explanations: (a) incorporation into proteins; (b) metabolism in- 
stead of efflux; (c) efflux from a cerebral space where the level of the amino acid is 
above that of plasma. 
(a) Control experiments with labeled amino acids!’ showed that the incorporation 
of the excess amino acid into protein—an unlikely event requiring net protein syn- 
thesis in the non-growing adult brain—did not occur. Of the label that penetrated 
maximally into the brain after one hour, 8% was incorporated into proteins, 10°% 
was still left in the free amino acid fraction, and 82°, left the brain. 
(b) In the experiments on cerebral metabolism of the amino acids, the labeled 
amino acids were found to be present as such in the brain and no significant amount 
of other labeled metabolites could be found?®, Decrease in cerebral levels may have 
occurred through slower metabolism and rapid exit of the formed metabolites from 
the brain, in which case no metabolic products would be found in the brain. Such an 
explanation does not seem very likely in these short-term experiments with amino 
acids that are not metabolized rapidly. 
(c) The intracerebrally administered amino acid, instead of being restricted to 
the area near the site of administration, was found to be distributed throughout the 
brain, in one experiment evenly in the six gross parts, im another experiment evenly 
in the seven vertical sections into which the brain was divided!®: 26. The restriction 
to the extracellular space is also not very likely since some of the label did get in- 
corporated into cellular proteins. A restriction to a glial space is not likely, since to 
explain the different plasma to brain ratios at equilibrium (13 for leucine, 5.6 for 
lysine, 1.7 or 7.7 for phenylalanine) a glial space of different size would have to be 
postulated for each of the three amino acids studied. 
The present experiments cannot establish the place where the transport against a 
concentration gradient occurs. Determination of a fraction of the cerebrospinal fluid 
(CSF) showed a rapid disappearance from the CSF as well?®, but the transport can 
occur between brain and plasma, brain and CSF, or CSF and plasma. Active transport 
of diodrast and phenolsulfonphthalein from CSF to blood was shown recently?’, with 
the site of active transport possibly at the choroid plexus of the 4th ventricle. 
The existence of active transport mechanism in amino acid transport in brain 
slices has been known for some time. That slices can accumulate amino acids against 
a concentration gradient has been shown for L-glutamate®, D-glutamate?’, y-amino- 
butyrate’: §, aspartate*®, tyrosine", histidine, proline, lysine, ornithine, methionine, 
and arginine*’, and 5-hydroxytryptophan*!. Interference with the source of energy 
decreased the rate of entrance and the net uptake of the amino acids in most of these 
experiments. The transport of amino acids from the brain against a concentration 
gradient 7m vivo (Figs. I, 2), the active transport of substances from the CSF’, the 
inhibition of tyrosine uptake 7 vivo by other amino acids**, and the effects on ex- 
change (Table I) show that the active and carrier mediated processes are operative 
in the living brain as well, perhaps in the passage of all amino acids. The active 
transport from the brain!” shows that these processes operate in both directions. 
Both exchange and net unidirectional flow theoretically permit that influx or efflux 
should be governed by the same mechanism; flux rate in any one direction may be 
individually controlled. It is of interest to recall in this respect that under certain 
References p. 563 
