Amino acid transmitters in the mammalian central nervous system

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152 D.R. CURTIS and G. A. R. JOHNSTON : flat vesicles, in glial cells, interneurones which appear not to accumulate the amino acid in slices, whereas motoneurones show little activity (LJuNaDAHL and H6KFELT, 1973). Uptake into Alia and neurones has also been found in cultures of rat spinal cord (H6SLI, LJUN~DAHL, H6KEELT, and H0SLI, 1972), and all of these observations are consistent with the uptake of glycine by inhibitory nerve terminals and interneurones. An enhanced effiux of glycine has been shown to follow direct electrical stimulation of spinal cord slices (Rat: HOPKIN and NEAL, 1971; CUTLER, HAMMER- STAD, CORNICK, and MURRAY, 1971 ; HAMMERSTAD et al., 1971). A calcium dependent effiux of glycine (and GABA, glutamate and asparate) was produced by electrical stimulation of the rostral portion of isolated, hemisected frog or toad spinal cords (ROBERTS and MITCHELL, 1972), or of dorsal roots (APRISON, 1970). It is difficult to relate these studies directly to mammalian cord in vivo, and of more significance is the release of exogenous glycine into the central canal of cats, in the presence of p-hydroxymercuribenzoate, and in association with acetylcholine, by stimulation of the femoral and sciatic nerves (JORDAN and WEBSTER, 1971). The organic mercurial was essential to demonstrate this enhanced release ofglycine, suggesting that a highly efficient uptake mechanism was present for the removal of this amino acid after synaptic release. 4.12.1.4. GABA The levels of GABA in the dorsal grey exceed those ventrally (Table 8), and detailed analysis of small blocks of tissue show that the highest levels (2.2- 2.6/~mole/g) occur in laminae III and IV (Cat: MIYATA and OTSUKA, 1972; OTSUKA and MIYATA, 1972). Although low relative to the concentration within Deiters' (6.3 mM) and Purkinje (6.0 mM) cells, the GABA concentration of dissected motoneurones (0.9) exceeds that of spinal ganglion cells (0.2, Cat: OTSUKA et al., 1971), and the technique almost certainly underestimates any contribution made by axodendritic synapses. The high dorsal concentrations of GABA correspond to those of GAD (Table 9, also Monkey: ALBERS and BRADY, 1959) whereas GABA-T is more uniformly distributed in the grey matter (Table 9). In the rhesus monkey, however, transaminase levels are somewhat higher dorsally than ventrally (SALVADOR and ALBERS, 1959). Following aortic occlusion, no significant alterations occurred in spinal GABA levels (Table 8), which is consistent with preservation of neurones in the superficial layers of the dorsal horn. On the other hand cauterization of the vessels supplying the dorsal horn, which suppressed generation of dorsal root potentials by afferent volleys, significantly reduced the dorsal horn content of GABA, the levels of other amino acids not being reported (MIYATA and OTSUKA, 1972). Extensive deafferentation of the rat's cervical cord resulted in reduced GABA levels, a marked reduction of GAD activity, reduced GABA transaminase activity and a reduced uptake of GABA into synaptosomes of tissue located in the dorso-lateral portion of the cord. There was also considerable reduction of GAD activity in ventral segments, and although the findings are suggestive of a loss of GABA-containing nerve terminals of either fibres in the dorsal root or of inhibitory interneurones
Amino Acid Transmitters in the Mammalian Central Nervous System 153 degenerating as a consequence of deafferentation (GoTTESFELD, KELLY, and RAYNER, 1973a), changes resulting from damage to the vascular supply need to be excluded. Only a high affinity uptake mechanism specific for GABA has been demonstrated in cat spinal tissue (BALCAR and JOHNSTON, 1973), into particles having a density characteristic of nerve terminals (Rat: IVERSEN and JOHNSTON, 1971 ; ARREGUI et al., 1972) which can be distinguished from those accumulating other amino acids. In autographic studies of spinal cord slices the principal site of GABA uptake appears to be nerve terminals (Rat: IVERSEN and BLOOM, 1972) which could not be classified morphologically but differ from those taking up glycine. In spinal cord cultures GABA is accumulated mainly by small neurones (HOSLI et al., 1972). 4.12.1.5. Other Amino Acids The distribution of the other amino acids present in spinal tissue does not suggest major roles as synaptic transmitters: ~-alanine, cystathionine and serine (Table 8), and taurine (Rat: spinal grey 1.6 ,umole/g, white 1.9, SHANK and APRISON, 1970). There are additionally other unidentified amino acids which may require further investigation (see BRIEL and NEUHOFF, 1972). A polypeptide has recently been extracted from bovine dorsal roots, but not from ventral roots, which is similar chemically and pharmacologically to physalaemin (OTSUKA, KONISHI, and TAKAHASHI, 1972; see also LEMBECK and ZETLER, 1962) and which, like physalaemin (KONtSHI and O'rSUKA, 1971) has a direct depolarizing action on motoneurones of the isolated frog spinal cord and dilates blood vessels. 4.12.2. Excitation Since the first demonstration of the direct depolarizing action on spinal motoneurones of electrophoretic L-glutamate, L-aspartate and L-cysteate (Cat: CURTIS et al, 1960), a number of investigations have been concerned with the excitation of spinal motoneurones, interneurones and Renshaw cells by these and related amino acids. Most emphasis has naturally been placed on L-glutamate and L- aspartate because of the neurochemical evidence discussed earlier. Differences in relative potencies have been related to the effectiveness of the amino acidreceptor interaction (CURTIS and WATKINS, 1960, 1963) and to the inactivation of amino acids in the tissue (CURTIS et al., 1970b). However, whilst in general L-glutamate and L-aspartate are approximately equipotent as excitants of spinal dorsal horn interneurones, L-aspartate is significantly more active than L-glutamate as an excitant of Renshaw cells (Cat: DU6aAN, 1974). This important observation is consistent with the operation of L-glutamate as the transmitter of primary afferent fibres, which do not synapse directly with Renshaw cells (see CURTIS and RYALL, 1966a), whereas L-aspartate may be the transmitter of spinal excitatory interneurones (DAvIDOFF et al., 1967). Sympathetic (Cat: HONCO and RYALL, 1966) and parasympathetic (DE GROAT and RYALL, 1968) preganglionic spinal neurones are excited by DL-homocysteate, and both L-glutamate and Dg-homocysteate increase the excitability of the terminal portions of primary afferent fibres (Cat: CURTIS and RYALL, 1966b). Depolarization of primary afferent fibres by L-glutamate has also been demonstrated in isolated preparations of amphibian spinal cord (SCHMIm', 1963; TEBF, CIS and PHILLIS, 1969; DAVIDOFF, 1972 d; BARKER and NICOLL, 1973).
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