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HANDBOOK OF PHYSIOLOGY ^ NEUROPHYSIOLOGY 1 



were able to antagonize increasing concentrations of 

 nicotine over a wide range of such concentrations, 

 and that the effects of the two substances were to some 

 extent reversible, the same result being achieved 

 irrespective of the order of their application. This led 

 to the suggestion that nicotine and curare competed 

 with each other in forming a loose combination with 

 a 'receptor substance,' which was thought to occur in 

 the muscle fiber immediately around the nerve 

 endings where it could be acted upon h\ the nerve 

 impulse. Nicotine or the nerve impulse when acting 

 on this receptor would lead to a contraction, while 

 its combination with curare would prevent either of 

 them being effective. 



In 1936 the concept of a distinctive chemical process 

 in neuromuscular transmission was given a secure 

 foundation by the work of Dale and his followers. 

 They succeeded in showing that a nerve impulse on 

 reaching the terminals in a muscle caused the release 

 of a pharmacologically active substance (iS). On the 

 repetitive stimulation of the motor nerve fibers, to the 

 exclusion of other types of nerve fibers, a substance 

 appeared in the fluid perfusing the muscle that was 

 capable of causing a contraction of muscle from the 

 leech and a fall in arterial pressure of the cat. From 

 the relative effectiveness of the substance on these two 

 test preparations and the modification in their 

 response produced by drugs, as well as from the chemi- 

 cal stability of the substance under various condi- 

 tions, it was concluded to be acetylcholine, the 

 pharmacological action of which was already known. 

 Its release was found to be undiminished when trans- 

 mission was abolished by curare. Further experi- 

 ments showed that the rapid injection of acetylcholine 

 into a muscle by its blood vessels caused the excitation 

 of muscle fibers and a contraction (7, 8, 9). This 

 occurred in the chronically denervated muscle as 

 well as in the normal one, and, as in the case of 

 nicotine, this excitatory action could be abolished by 

 curare. The effect of physostigmine was also ex- 

 amined. It was found to prolong and intensify the 

 response to injected acetylcholine and to cause repeti- 

 tive muscle discharges to a single nerve impulse. 

 From earlier studies it was known that physostigmine 

 has the specific action of inhibiting the enzyme that 

 destroys acetylcholine. 



All these findings are compatible with the chemical 

 theory of transmission, according to which transmis- 

 sion is accomplished by the nerve impulse causing the 

 release of a small quantity of acetylcholine from the 

 nerve endings. This substance combines with a special 

 receptor substance in the junctional region of the 



muscle fiber and, by so doing, alters the properties 

 of the fiber in such a way as to lead to excitation and 

 contraction. This mediation of transmission by a 

 specific chemical is fundamentally different from the 

 process occurring when an impulse is conducted along 

 a continuous structure, in which case an essential 

 factor for the spread of excitation is a flow of electric 

 current between adjacent parts. An alternative 

 explanation of neuromuscular transmission is ex- 

 pressed in the electrical theory, according to which 

 transmission is affected by the action currents gen- 

 erated by the impulse in the prejunctional nerve 

 terminals passing through the adjacent muscle fiber 

 in the appropriate direction and in sufficient magni- 

 tude to cause excitation. This theory was formulated 

 when the electrical events associated with the con- 

 ducted impulse were first studied, and the attempt 

 was made to account for both processes by a common 

 mechanism. The selective sensitivity of transmission to 

 various treatments was ascriljed to secondary effects, 

 in particular to the alteration of the electrical ex- 

 citability of the postjunctional structure. 



The results of experiments in which chemicals are 

 involved, either the collection of acetylcholine after 

 nerve stimulation or the application of various 

 chemicals to evoke or modify the response of the 

 postjunctional structure, are consistent with the 

 chemical theory. A decisive result which excludes the 

 possibility of electrical transmission comes from the 

 study of the alteration of properties of the post- 

 junctional region during transmission. It is found that 

 the characteristic alteration responsible for excitation 

 of the muscle fiber cannot be brought about by a 

 current generated externally to the fiber. On the other 

 hand an alteration of precisely this type is produced 

 by the application of acetylcholine to the junctional 

 region of the muscle fiber. Accepting the correctness 

 of the chemical theory of transmission, one is able to 

 give an integrated account of a wide range of experi- 

 mental observation, distinguishing between those 

 events which occur prejunctionally and involve the 

 release of acetylcholine, and those which occur post- 

 junctionally and involve the reaction of acetylcholine 

 with the receptor and the resultant change in the 

 properties of the muscle fiber membrane. 



MORPHOLOGY 



The detailed morphological description which fol- 

 lows applies to junctions on skeletal muscle in verte- 

 brates where the normal response to a single nerve 



