PSYCHOTROPIC DRUGS AND THE METABOLISM OF BRAIN 497 
An explanation might be that those enzymes are involved which determine the 
GABA and Glu levels. Orphenadrine was investigated for this purpose. No effect 
could be established on L-glutamic acid decarboxylase!® and pyridoxal kinase; the 
effect on GABA—a-ketoglutaric acid transaminase is still being investigated. However, 
orphenadrine, at the test concentration (2mWM), inhibits the ATP-ase while it 
uncouples oxidative phosphorylation. This does not imply, however, that uncoupling 
oxidative phosphorylation invariably prevents the resorption of the amino acids. 
Thus, DNP (ref. 20), benactyzine, captodiamin and meprobamate?!, at concentra- 
tions which uncouple oxidative phosphorylation, do not interfere with GABA and 
Glu resorption. We do not know to what extent changes in permeability of the cell 
membrane affect the resorption. Orphenadrine is known to reduce the permeability 
of the blood—brain barrier for 74Na in rats?*. 
This was also established by LIEBALDT?? with respect to the dye Evans Blue, 
during tests with dogs and rabbits. According to LIEBALDT this provides an ex- 
planation for the clinically established suppression of the reserpine-induced ex- 
trapyramidal effects. This substance appeared to increase the permeability for 
Evans Blue. A combination of reserpine and orphenadrine normalises the enhanced 
permeability. 
During our investigations spectrophotometric determination of Evans Blue 
eluted from the brain tissue*4 showed that this dye is less well resorbed by the brain 
after administration of orphenadrine than in control animals; under the influence 
of orphenadrine the dye resorption decreased by approx. 20%. 
In addition, preliminary results may be mentioned of some other recent investiga- 
tions at our laboratories. 
As reported by Roperts®® administration of hydroxylamine to rats causes an 
increase in the metrazol seizure threshold while GABA levels in the brain rise con- 
comitantly. 
As we have been able to establish, rabbits also show such an increase in metrazol 
seizure threshold after administration of hydroxylamine (although in this case 
GABA levels remain unaffected). 
Orphenadrine causes a transient lowering of the metrazol seizure threshold which 
returns to former levels in approx. 2h time. However, when hydroxylamine is 
administered at that moment it fails to exert its expected effect on the seizure 
threshold. Although it would seem, therefore, that the gross GABA level is not 
determinative for the metrazol seizure threshold, orphenadrine evidently interacts 
with the system linking convulsion liability with GABA and hydroxylamine, 
perhaps by way of its influence on permeability, which may result in GABA being 
not available at its site of action. 
Whether changes in permeability also play a part in the 7m vitro tests on resorption 
of amino acids must remain an open question for the time being. 
We are trying to gain a better insight by measuring the resorption rate of the *4Na 
added to the incubation medium. Further, it is uncertain whether the 77 vitro effect 
of psychotropic drugs on the amino acid levels is in any way related to the action 
mechanism of these drugs in the intact organism. 
References p. 498 
