THE IDENTIFICATION OF 

 MAMMALIAN INHIBITORY TRANSMITTERS 



David R. Curtis 



Departments of Physiology, The Australian National University, Canberra, and 

 Downstate Medical Center, State University of New York, Brooklyn, New York 



The purpose of this communication is to discuss the methods by which 

 inhibitory transmitters of the mammahan central nervous system may be 

 identified. It will be assumed that apart from the depression of neuron 

 excitability which occurs during the refractory period following a spike, the 

 modifications of this excitabihty are normally purely synaptic processes and 

 that synaptic inhibition is the consequence of an increase in the permeability 

 of specialized areas of the postsynaptic membrane following the production 

 of an inhibitory transmitter-receptor complex (Eccles, 1957, 1959; Grundfest, 

 1959). Inhibitory substances therefore differ from a series of compounds, 

 classified as depressants, which lower the excitability of neurons in the 

 absence of such a specific permeability increase. 



The criteria, all of which must be satisfied before a substance can be 

 established as a transmitter, are based upon the methods by which acetyl- 

 chohne was shown to be a transmitter at the neuromuscular junction and in 

 autonomic gangha (Feldberg, 1951 ; del Castillo and Katz, 1956; Eccles, 1957; 

 Elkes, 1957;Crossland, 1957;Paton, 1958;Koel]e, 1959; Curtis and Watkins, 

 1960a). It is proposed to discuss these individually in terms of the special 

 conditions imposed by the location of neurons within the nervous system. 

 The order in which these points will be treated has been determined mainly 

 by the practicability of estabHshing methods by means of which the various 

 criteria can be tested. The use of relatively simple neurophysiological tech- 

 niques may help to limit the number of substances to which the rather more 

 difficult chemical and assay procedures need be appHed, assuming, however, 

 that the substance being investigated has been selected as a possible trans- 

 mitter because of either its presence or the presence of a structurally similar 

 compound in brain extracts or because of pharmacological observations of 

 its action upon the activity of neurons. 



A. THE ACTION OF THE SUBSTANCE UPON NEURONS 



MUST BE IDENTICAL WITH THAT OF THE INHIBITORY 



TRANSMITTER ACTING UPON THESE CELLS 



Many chemical agents are capable of diminishing the responses of neurons 

 to excitatory synaptic action but the process of inhibition is associated with a 



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