Amino acid transmitters in the mammalian central nervous system

104 D.R. CURTIS and G. A. R. JOHNSTON :
acid may 1/ave different antagonists at different receptors, and that an antagonist
of an amino acid in one species may not necessarily be effective in another.
Care is also required to exclude the formation of relatively stable amino acid/
antagonist complexes as an explanation of antagonism. Although it may not be
possible by microelectrophoretic methods alone to establish the mechanism of
antagonism (CURTIS, DUGGAN, and JOHNSTON, 1971 c), the structure of antagonists
may provide some evidence regarding the nature of amino acid receptors
(SMYTHIES, 1971). Both this type of study, and proposals regarding the nature of
the transmitter, are strengthened when there is a direct correlation between the
potencies as amino acid antagonists of a series of substances of similar or different
structure and their effectiveness in suppressing synaptic action.
One major problem concerned with the use of antagonists is the method
of administration, both for establishing the mechanism and degree of selectivity
of the antagonism, and for blocking synaptic transmission. A highly selective
antagonist ejected from one orifice of a multibarrel micropipette may readily
block the effect of one amino acid and not of others ejected from adjacent
orifices, yet may apparently have little action on the effect of the same amino
acid released synaptically because the antagonist gains access to too few synapses
(CURTIS et al., 1971c; CURTIS, 1971). On the other hand, if the antagonist is
administered systemically, and local concentrations are sufficient to significantly
modify synaptic transmission, these may not be adequate to influence the effects
of localized and relatively high concentrations of electrophoretically administered
amino acids. Potentially useful antagonists may not penetrate the blood brain
barrier, and the dose of a systemically administered compound may be severely
limited by general effects on the experimental animal and actions at synapses
other than those being studied. Neither method of administration is ideal for
determining the selectivity of an antagonist in such a complex tissue as the
CNS. The estimations can best be considered no more than indications of the
probability that the suppression of a synaptic event involves the participation
of one amino acid, and not another, as the transmitter.
Accepting these restrictions, strychnine and some related compounds are useful
antagonists at sites where glycine is the transmitter, and bicuculline and
picrotoxinin, where GABA is involved. These and other agents are discussed
in more detail in subsequent sections. At the present time no satisfactory antagonist
has been found which distinguishes between aspartate and glutamate as
neuronal excitants, and the specificity of those agents proposed as selective antagonists
of excitant amino acids seems doubtful.
2.5. Inactivation and Removal
There is no evidence to indicate that amino acids are inactivated enzymically
in the extracellular synaptic environment, and a number of observations suggest
that carrier mediated cellular uptake (see WYSSBROD, SCOTT, BRODSKY, and
SCHWARTZ, 1971), which may involve membrane bound enzymes as binding
sites (MEISTER, 1973), might be responsible for limiting the immediate action
of amino acids in the subsynaptic region and for preventing accumulation of