SYNAPTIC AND EPHAPTIC TRANSMISSION 



'79 



body. Likewise, interest in GABA stems from the 

 demonstration of its occurrence in the brain in an 

 important pathway of synthesis (12, 172). Thus, the 

 candidate for a transmitter agent must meet a num- 

 ber of requirements (cf. also 65): a) it must mimic 

 closely the actions produced by the natural, neural 

 stimulus; b') its actions must be affected by the same 

 drugs and in the same ways as neural excitation is 

 modified; c) it must be a naturally occurring con- 

 stitutent, found in close proximity to the relevant 

 synaptic structures; and (/) it is desirable to demon- 

 strate that it is formed by an appropriate metabolic 

 pathway, that it is released at the time, place and in 

 the degree suitable to transmitter action and that its 

 accumulation to excess is prevented by another 

 metabolic pathway. 



Characterized by the foregoing criteria, acetyl- 

 choline and the catechol amines of the epinephrine 

 group are still the only substances commonly agreed 

 upon and accepted as peripheral transmitter agents. 

 Most conspicuously, these substances derive their 

 claim to transmitter agents by their actions as 

 synapse activators. Thus, acetylcholine is probably 

 the excitatory transmitter at electroplaques, muscle 

 fibers, autonomic ganglia and some gland cells. At 

 the effector junctions of the cardiac pacemaker and 

 probably also in many smooth muscle systems (96), 

 acetylcholine activates hyperpolarizing synapses and 

 is inhibitory. The epinephrine group of transmitters 

 acts similarly at other synapses. However, these 

 transmitters also appear to have an accessory func- 

 tion (cf. 36). Thus epinephrine may antagonize the 

 action of decamethonium (47) or relieve ' fatigue' of 

 neuromuscular transmission upon repetitive stimula- 

 tion (119).^ 



In complex synaptic systems, one may as.sign 

 transmitter action to substances which do inac- 

 tivate synapses. For example, GABA is a synapse in- 

 activator, but if it is released by specific nerve fibers 

 its effects would be essentially inhibitory — with the 

 important exception that there would be no accom- 

 paniment of hyperpolarizing p.s.p. Likewise there 

 might be transmitters, analogous to Cg, whose overt 



^ Neuromuscular blockade by decamethonium is a manifes- 

 tation of Wedensky inhibition discussed earlier. Antagonism by 

 epinephrine suggests that this transmitter agent acts as a com- 

 petitive antagonist, or synapse inactivator, of cholinoceptive 

 synaptic membrane. This type of action is apparently contra- 

 dicted by the ciTect of epinephrine in lifting the blockade pro- 

 duced by repetitive activity. However, there need be no real 

 contradiction for synaptic membrane may change its properties 

 under different experimental circumstances, an indication of 

 the complexity as well as lability of the active structure (cf. 96). 



action, excitation, might be produced by inactivat- 

 ing hyperpolarizing inhibitory synapses. 



These considerations indicate the difficulty of 

 identifying transmitters in a complexly organized 

 synaptic structure. The difficulty is enormously com- 

 pounded in the central nervous system, where even 

 a small volume of tissue contains a huge number of 

 synapses. In such a case all the criteria for categoriz- 

 ing transmitters cannot be fulfilled at present and 

 therefore identification is always tentative, based as 

 it must be on incomplete evidence. 



Nevertheless, there is evidence from various sources 

 that acetylcholine and the adrenergic agents do af- 

 fect central nervous activity. Thus, circulatory injec- 

 tions of epinephrine (22) or acetylcholine (cf. iii) 

 bring about EEG activation as does stimulation of 

 the peripheral stump of the cat splanchnic nerve 

 (22). The electrical activity of a cortical slab, iso- 

 lated from its neural connections but surviving with 

 intact blood supply, is altered upon electrical stimu- 

 lation of the brain stem reticular formation (122). 

 Thus, brain stem activity releases some transmitter 

 agents which can then affect the isolated cortex. 

 This finding has been extended to cross-perfused 

 preparations (160). From that work it may be con- 

 cluded that what is released during brain stem ac- 

 tivity enters the systemic circulation and that it 

 must be a substance (or several) more stable than is 

 acetylcholine. The latter probably would have been 

 destroyed completely or almost so during the time 

 required for an exchange of circulating blood be- 

 tween donor and host. Many workers have shown 

 that acetylcholine is found in the central nervous 

 system as well as its synthesizing acetylating enzyme 

 (for references to the recent literature cf. 65). The 

 distributions of these substances in the brain and of 

 sympathetic transmitters (192) have also been 

 mapped. Lesions in some regions of the reticular 

 formation augment or depress the sensitivity of the 

 cortical electrical activity to epinephrine (178) 

 Intraventricular application of cholinomimetic and 

 adrenomimetic substances or of blockaders of the 

 two types of synapses produce a variety of central 

 nervous symptoms (cf. 75, and literature cited there). 

 Intravenous injections of (/-tubocurarine block cen- 

 tral nervous synapses (cf. 165). 



Evidence with respect to other agents is still in- 

 conclusive. Although 5-hydroxytryptamine (sero- 

 tonin) and metabolically related substances are be- 

 lieved by some to be implicated in transmission, 

 whether they act directly or not is still in question 

 (cf. 26, 128, 148). As stressed earlier in this part. 



