i8o 



HANDBOOK OF PHYSIOLOGY 



NEUROPHYSIOLOGY I 



the difficulties are largely methodological because 

 central synapses are so intricately interrelated and 

 may present many varieties. Stemming from this is 

 the difficulty of determining whether or not various 

 synaptic sites are afifected, and if they are what 

 results are to be looked for. Thus it has been shown 

 (162, 163) that the synaptically active amino acids 

 affect primarily only axodendritic synapses of the 

 cortex and only secondarily the axosomatic. Some 

 consecjuences are seen in figure 25. Blockade of ex- 

 citatory synapses of the dendrites by C4 (GABA) or 

 of inhibitory synapses by Ce (e-aminocaproic acid) 

 does not afTect the corticospinal discharge of the 

 pyramidal cells. However, the convulsive electro- 

 cortical activity induced by Cs (oj-aminocaprylic 

 acid) leads to prolonged discharge in the tract. 



A further difficulty is the problem of accessibility 

 of the central synapses to testing drugs. The blood- 

 brain barrier apparently is highly effective for some 





FIG. 25. Pyramidal tract activity when dendritic responses 

 in cerebral cortex are affected by u-amino acids. Column A, the 

 discharge recorded from the pyramidal tracts to stimulation of 

 the cerebral cortex in cats. Then, 0.2 cc of i per cent u-amino 

 acid had been applied for 10 min. The substances were C4 and 

 Cs as noted in each row of records. The responses of column B 

 were obtained when the cortical potentials had been altered as 

 shown in figs. 22 and 24. Despite these changes, the pyramidal 

 tract responses, generated by direct electrical stimuli and by 

 axosomatic synaptic excitations, were not affected (C4, Ce) 

 except when as in the case of C^, the drug caused convulsions. 

 Then a long after-dischsirge, associated with the convulsions, 

 developed. Ten superimposed traces in the upper records, five 

 in the middle and lower set. Time 10 msec. [From Purpura et 

 a/. (163).] 



substances, e.g. GABA [Roberts & Baxter (172)]. 

 Recent experiments (164) demonstrate that local 

 abolition of the blood-brain barrier permits the local 

 action of systemically injected oj-amino acids. These 

 results indicate that if the substances are elaborated 

 within the brain they might act as transmitters (using 

 the term for both synapse activators and inactivators; 

 cf. above), although the usual experimental criteria 

 would not disclose such action. 



Modes of Action of Transmitter Agents and Synaptic Drugs 



Since transmitters must be formed and, after their 

 release, metabolized in the body, enzymes for these 

 activities are components more or less related to the 

 appropriate synaptic systems. In the search for 

 mechanisms of drug action, interference with en- 

 zymatic or other metabolic processes has been fre- 

 quently stressed (cf. 2, 13, 14, 26, 65, and literature 

 cited in these papers). Undoubtedly-, interference 

 with these metabolic systems must cause synaptic 

 disturbance; but it is likely that such actions are 

 relatively slow, manifesting themselves, as in the 

 case of vitamin deficiences, only after depletion of 

 reserves. This is not the case with drugs that have 

 primary action on synapses (108). This may be .seen 

 in figures 22 to 24 in which the synaptic effects of 

 some of the oj-amino acids were obtained within a 

 second after they were applied and were rapidly 

 reversed by dilution. 



Furthermore, substances of the same type of action 

 on enzymatic systems may have entirely different 

 synaptic actions. Thus physostigmine, DFP and 

 prostigmine are powerful inhibitors of cholinesterase. 

 By that effect all three, in very high dilution, enhance 

 neural action in eel electroplaques (5). This is merely 

 the indication that they prolong the life of the labile 

 transmitter agent. However, the synaptic actions of 

 the three drugs on the eel electroplaque are diverse 

 (table 2). In that capacity prostigmine is a synapse 

 activator like acetylcholine itself Physostigmine js an 

 inactivator like (/-tubocurarine and about as potent 

 in that effect. DFP appears to have dual actions 

 such as are to be found in the many other situations 

 (cf. 95, 96, 127). 



The conclusion reached from these considerations 

 leads back to the view first proposed by Ehrlich (cf 

 2, 14, 40) that drugs exert their action by affecting, 

 perhaps by some form of chemical or electrostatic 

 combination, the performance of specific molecular 

 structures of the cell membrane. This receptor theory 

 has had many vicissitudes, apparently largely be- 

 cause of static conceptions of such functional units. 



