Amino acid transmitters in the mammalian central nervous system

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150 D.R. CURTIS and G. A. R. JOHNSTON: 4.12.1.1. Aspartate Within the cord ventral grey levels are higher than dorsal grey. An association with small neurones, presumably interneurones, has been suggested by the significant reduction in aspartate produced by temporary aortic occlusion, the reduced levels of this amino acid in dorsal and ventral grey matter correlating with the reduced count of small neurones in the central grey region (DAvIDOFF et al., 1967). As shown in Table 9 the activity of aspartate aminotransferase does not seem to correspond closely with that of the amino acid (Table 8). 4.12.1.2. Glutamate L-Glutamate is the only putative amino acid transmitter for which dorsal root levels exceed those of the ventral root (Table 8), as might be expected of a transmitter released by primary afferent fibres. Similar differences occur in the dog and rat (DUGGAN and JOHNSTON, 1970b). The high level of the amino acid in dorsal root ganglia, and the gradient along the root (Cat': ganglion 4.5 #mole/g, dorsal root distal to cord 4.5, proximal to cord 3.4, DUGGAN and JOHNSTON, 1970a), which contrasts to the approximately equal levels of other amino acids in peripheral nerves and dorsal roots (Table 8), suggests that glutamate synthesised in ganglion cells is transported towards central terminals. No such dorsal root gradient was present in thedog (DuGGAN and JOHNSTON, 1970b). Further investigation is warranted of the relationship to the possible transmitter function of glutamate of the influx into, and particularly the efflux from, stimulated peripheral nerves (WHEELER, BOYARSKY, and BROOKS, 1966; DEFEUDIS, 1971 ; WHEELER and BOYARSKY, 1971). After aortic occlusion, and loss of spinal interneurones, glutamate levels fall significantly in all segments of the cord, especially in the dorsal grey, but no correlation could be established between neurone loss and change in amino acid concentration (DAvIDOFF et al., 1967). Furthermore spinal glutamine levels were not modified (Table 8). The pattern of activity of glutamine synthetase and glutaminase (Table 9), enzymes associated with glutamate-glutamine interconversion, and of glutamate dehydrogenase, correspond with the distribution of glutamine, but not with that of glutamate (Table 8). Both high and low affinity uptake mechanisms are present in spinal tissue for acidic amino acids, the same high affinity process transporting L-glutamate and L-aspartate (Rat: LOGAN and SNYDER, 1972. Cat: BALCAR and JOHNSTON, 1973). Osmotically sensitive particles of density similar to that of nerve endings are in part responsible for this uptake, which in the cat is less sensitive to inhibition by p-chloromercuriphenylsulphonate than the high affinity uptake of either glycine or GABA. In the rat the particles accumulating aspartate and glutamate are denser than those accumulating glycine (ARREGUI et al., 1972). 4.12.1.3. Glycine In contrast to relatively low levels in dorsal and ventral roots, higher levels of glycine are found in the spinal grey matter, particularly ventrally (Table 8).
Amino Acid Transmitters in the Mammalian Central Nervous System 151 Furthermore, glycine levels are higher in the cord, and medulla, than elsewhere in the feline (SHANK and APRISON, 1970) and other vertebrate nervous systems (APRISON et al., 1969), and the highest intraspinal levels of glycine in the cat and other vertebrates correspond to regions of high grey matter to white matter ratio, regions containing neurones associated with limb innervation (also Human: BOEHlVIE, FORDICE, MARKS and VOGEL, 1973). Spinal white matter contains long descending and ascending tracts as well as the axons of propriospinal fibres. The dorsal column content of the latter is minimal (NATHAN and SMITH, 1959; SZENTAGOTHAI, 1964), and hence the low levels of glycine in this region (Cat: lumbar, 1.2 gravies/g) compared with dorsolateral (4.6), ventrolateral (5.6) and ventromedian white regions (3.5) (APRISON et al., 1969) suggests that glycine-containing propriospinal axons account for the relatively high levets of this amino acid in the lateral and ventromedial tracts. A strong association between glycine and spinal interneurones was established by the very significant reduction observed in dorsal grey, ventral grey and ventral white segments (Table 8) following temporary aortic occlusion in the cat and destruction of neurones in the central region of the cord (DAvIDOFF et al., 1967). The ventrolateral white area is rich in propriospinal fibres, and there was a statistically significant correlation between the concentration of glycine in the grey matter and the number of small neurones remaining after anoxic destruction. Of enzyme activities associated with glycine metabolism, spinal tissue contains glycine transaminase (glycine: 2-oxoglutarate transaminase: JOHNSTON and VITALI, 1969 a, JOHNSTON et al., 1970; BENUCK et al., 1972), serine hydroxymethyltransferase (SHANK and APRISON, 1970; DAVIES and JOHNSTON, 1973), D-glycerate dehydrogenase and D-3-phosphoglycerate dehydrogenase (UHR and SNEDDON, 1971, 1972) and glycine decarboxylase (UHR, 1973). Glycine is also a poor substrate of D-aminoacid oxidase (Cat: DE MARCHI and JOHNSTON, 1969). The regional distributions of neither glycine transaminase nor serine hydroxymethyltransferase correlate with that of glycine in the cord (Table 9). In vivo studies of glycine metabolism in the rat cord suggest that glycine is synthesised only slowly from glucose (SHANt~ and APRISON, 1970; SHANK et al., 1973). A number of investigations have been concerned with the high affinity structurally specific uptake of glycine by spinal tissue, a process mainly confined to the cord, medulla and pons (Rat: NEAL, 1971; IVERSEN and JOHNSTON, 1971; JOHNSTON and IVERSEN, 1971; LOGAN and SNYDER, 1972; ARREGUI, et al., 1972; APRISON and MCBRIDE, 1973. Cat: BALCAR and JOHNSTON, 1973). The subcellular particles associated with this uptake are denser than those accumulating GABA but less dense than those taking up aspartate and glutamate (Rat: IVERSEN and JOHNSTON, 1971 ; ARREGVI et al., 1972). Radioautographic analyses of the uptake of labelled glycine by spinal cord slices in vitro shows that the uptake is highest in the ventral horn particularly around motoneurone bodies, with intense uptake into nerve terminals (Rat: MATUS and DENNISON, 1972 ; H6KFELT and LJUNGDAHL, 1971 a) which differ from those accumulating GABA (Rat: IVERSEN and BLOOM, 1972). In one study all labelled terminals contained flat vesicles, some 60% of flat vesicle synapses accumulating the labelled amino acid (MATVS and DENNI- SON, 1972). Under in vivo conditions, following direct injection of labelled glycine into the cat spinal cord, the amino acid is present in nerve terminals containing
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Amino acid transmitters in the mammalian central nervous system

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