Amino acid transmitters in the mammalian central nervous system

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120 D.R. CURTlS and G. A. R. JOHNSTON : et al., 1971). Furthermore the natural occurrence of D-glutamate and D-aspartate in CNS tissue has not been excluded (CORRIGAN, 1969). L-Cysteate. The sulphonic acid analogue of L:aspartate is present in low concentration (approx. 0.1 /~mole/g) in extracts of rat brain (MussINI and MARCU¢¢k 1962; MANDEL and MARK, 1965). This amino acid depolarizes feline spinal motoneurones and is comparable in potency to L-aspartate (CURTIS et al., 1960). In general, L-cysteate may be metabolised by two pathways: decarboxylation to taurine or transamination with a-oxo acids (GAITONDE, 1970). L-Cysteate is a strong competitive inhibitor of the high affinity uptake of L-glutamate by rat brain slices and thus could be a substrate for this transport system (BALCAR and JOHNSTON, 1972 b). L-Cysteate produces acute neuronal degeneration in the hypothalamus of infant mice following subcutaneous administration (OLNEY et al., 1971). L-Cysteine Sulphinate. This acidic amino acid, which has been detected in rat brain (BERGERET and CHAXAGNE, 1954)is a powerful excitant of spinal neurones (Cat: CURTIS and WATKINS, 1963) and a powerful competitive inhibitor of the high affinity uptake of L-glutamate by rat brain slices (BALeAR and JOHNSTON, 1972b). The enzyme L-cysteine sulphinate decarboxylase, which produces hypotaurine from L-cysteine sulphinate, occurs in rat brain associated with synaptosomes (AGRAWAL et al., 1971). The complex metabolic interrelations of L-cysteine sulphinate, L-cysteate, taurine and hypotaurine are discussed by GAITONDE (1970). Subcutaneous administration of L-cysteine sulphinate is followed by degeneration in the hypothalamus of infant mice (OLN~Y, HO and RHEE, 1971). 4. Anatomical Organization of Amino Acid Transmitters 4.1. Cerebral Cortex 4.1.1. Excitation Although cortical glutamate levels (Table 2), are amongst the highest for mammalian tissues, little evidence is currently available to associate regional differences in the levels of either glutamate or aspartate with terminals of interneurones or particular afferent fibres. Such arl association with fibres projecting to the cortex is suggested bY the reduced levels of both amino acids (and GABA) which follows undercutting of the suprasylvian gyrus in the cat (BERL and MCMVRTRY, 1967), although the reduced glutamate levels of the motor cortex of the cat as a result of tetanic stimulation of the thalamic ventrolateral nucleus have been interpreted largely in terms of energy metabolism (CONSTANTINESCU, FLOR~SCU, and HATEGANU, 1970). The moderate levels of glutamate in the corpus callosum and the posterior portion of the internal capsule (Table 2), which exceed those of the dorsal root, may indicate the presence of glutamate releasing fibres; the low level in the peduncles suggest that the fibres of the pyramidal tract may not be of this type. Subcellular distribution studies have hitherto failed to demonstrate any selective storage of either aspartate or glutamate within nerve endings (synaptosomes) of the cerebral cortex (Rat: RYALL, 1964. Guinea pig: RYALL, 1964 ; MANGAN and WHITTAKER, 1966; see also KRNJEVIC and WHITTAKER, 1965; WHITTAKER, 1968). Both amino acids, however, are accumulated from low extracellular concentrations by a subcellular fraction of homogenates of this tissue which may be largely synaptosomal in nature, and can be distinquished from fractions accumulating other amino acids (Rat: WOFSEY et al., 1971). This "high affinity"
Amino Acid Transmitters in the Mammalian Central Nervous System 121 Tabel 2. Excitant amino acids in regions of cerebral cortex (gmole/g, *Biopsy) Region Animal Aspar- Gluta- Reference rate mate Frontal Human 1.9 8.9 PERRY et al. (1971 a) Occipital Human 2.6 8.6 PERRY et al. (t971 a) Temporal Human 1.9 10.8 PERRY et al. (1971 a) Temporal Cat 3.1 12.9 BATT1ST1N et al. (1969) Suprasylvian Cat 2.9 10.5 BERL and McMVRXRY (1967) Post Cruciate Cat 2.7 10.3 VAN G~LDER (1972) Association Cat 1.5" 6.0* PERRY et al. (1972) Motor Cat t.6' 5.5* PERRY et al. (1972) Visual Cat 1.8" 5.9* PERRY et al. (1972) Primary auditory Cat 10.7 JOHNSON and APRISON (1971) Primary somatosensory Cat 10.2 JOHNSON and APRISON (1971 ) Sylvian ectosytvian Cat 13.0 JOHNSON and APRISON (1971) Various areas Cat 2.3* 9.7* KOYAMA (1972) Corpus callosum Cat 5.9 JOHNSON and APRISON (1971) Corpus callosum Cat 1.4 10.6 BATTISTIN et al. (1969) Peduncle Cat 3.7 JOHNSON and AeRISON (1971) Internal capsule Cat 5.6 JOHNSON and APRISON (1971) (posterior) uptake, which has also been studied in slices of cerebral cortex (Rat: BALCAR and JOHNSTON, 1972b) is absolutely sodium dependent (BENNETT et al., 1972). Both glutamate and aspartate are released from the exposed and superfused cerebral cortex of neuroaxially intact cats, the rates being higher in aroused than in sleeping animals (JASPER, KHAN, and ELLIOTT, 1965; JASPER and KOYAMA, 1969). Rates of release in resting encephale isol6 preparations were comparable with those of intact sleeping animals, and were considerably.enhanced by stimulation of the mesencephalic reticular formation, which simulated arousal, but not by stimulation of the medial thalamic recruiting system. Since both kinds of stimulation increase the cortical release of acetylcholine, separate cholinergic and excitant amino acid-releasing "activating" pathways have been proposed (JASPER and KOYAMA, 1969). However, reciprocal alterations in the rate of GABA release were also recorded, and changes in amino acid release from the cortical surface may not necessarily be a direct measure of that released synaptically. Glutamate is also released from the cortical surface during spreading depression (VAN HARREVELD and KOOIMAN, 1965), and there is an extensive literature concerning a possible association between excitant amino acids and this abnormal state in both the cortex and retina (VAN HARREVELD, 1970; VAN HARREVELD and FIFKOVA, 1972; PHILHS and OCHS, 1971 ; Do CARMO and LE~.O, 1972). The excitatory effect of glutamate and aspartate on the cortex was first demonstrated after intracortical or intracarotid injection (OKO~OTO, 1951; ITO, TANI, SATO, and ODA, 1952; HAYASHI, 1952). Such an action also accounts for the effects of topically (Rabbit: VAN HARREVELD, 1959. Cat: PURPURA, GIRADO, SMITH, CALLAN, and GRUNDFEST, 1959) or intraventricularly (see CURTIS and WATKINS, 1965) administered acidic amino acids, and direct excitation was subsequently confirmed at the cellular level in microelectrophoretic studies (Cat: KRNJEVIC and PHILLIS, 1963 ; KRNJEVIC, 1964; CRAWFORD and CURTIS, 1964). The
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