Amino acid transmitters in the mammalian central nervous system

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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
Amino Acid Transmitters in the Mammalian Central Nervous System 105 amino acids in the extraneuronal space (IVERSEN and NEAL, 1968; CURTIS, DUG- GAY, and JOHNSTON, 1970b; SNYDER et al., 1972). Uptake by synaptic terminals could provide a supply of transmitter for re-use, there are indications however that glial uptake can also take place (HENN and HAMBERGER, 1971). If local inactivation of amino acid transmitters occurs, selective inhibition of the uptake of an amino acid should lead to enhancement and prolongation of its effects after both synaptic release and artificial administration. This has yet to be achieved in a selective fashion for any of the amino acid transmitters, largely because close structural analogues which are themselves transported, so inhibiting the accumulation of the putative transmitter, have postsynaptic actions similar to that of the transmitter. The uptake of radiolabelled amino acids has been studied using tissue slices or particulate matter in homogenates (COHEN and LAJTHA, 1972). Such in vitro methods, convenient for studying kinetics of the process and to assess the action of possible antagonists, maynot, however, be directly applicable to processes occuring in vivo, particularly as CNS tissue has complex metabolic, ionic and organizational requirements. Thus analyses of the cellular distribution of radio labelled amino acids after direct in vivo injection (see Section 2.2) offer a better indication of the sites of uptake (HOKFELT and LJUNGDAHL, 1972b). Structurally specific uptake systems (COHEN and LAJTHA, 1972) fall into two groups on the basis of their kinetic parameters, subcellular and regional distributions. The first group is characterised by Km's higher than 5 x 10- 4M, and appear to be similar to those found in other than CNS tissues. The second group has Km'S lower than 5x 10-SM: these "high at'finity" systems, which are sodium dependent, have been found specific for the amino acids considered most likely to be transmitters, GABA, glycine, taurine and L-glutamate/L-aspartate, and appear to be associated with distinct populations of subcellular particles -- nerve terminals and/or glial elements. The cellular accumulation or uptake of amino acids is accompanied by a movement of ions across the membrane (CHRISTENSEN, 1970, 1972), but it has become apparent that this process differs in several respects from the ionic permeability increase responsible for excitation or inhibition by amino acids. In the first place, strychnine, picrotoxinin and bicuculline interfere with the inhibitory actions of glycine and GABA, but have not been found to modify the uptake of these amino acids by nervous tissue (Cat: BALCAR and JOI~NSTON, 1973). Secondly, although groups of structurally similar amino acids are transported by common carrier mechanisms (COHEN and LAJTHA, 1972), and to some extent the structural requirements seem similar to those necessary for interaction with receptors for excitation or inhibition (CURTIS and WATK~S, 1965), a number of potent agonists of amino acid action are weak or relatively ineffective inhibitors of the uptake of the related naturally occuring amino acids. Thus D-homocysteate and N-methyl-D-aspartate are unlikely to be transported by the L-glutamate/ aspartate system (BALCAR and JOHNSTON, 1972a), yet both are potent excitants (CURTIS and WATKINS, 1965). Additionally 3-aminopropane sulphonate has little effect on GABA uptake yet is a potent GABA-Iike depressant (BEART and JOHN- STON, 1973 b). A direct relationship would be expected between uptake and postsynaptic action if excitation or inhibition by an amino acid directly involved
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Amino acid transmitters in the mammalian central nervous system

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