Amino acid transmitters in the mammalian central nervous system

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124 D.R. CURTIS and G.A.R. JOHNSTON: strated in rat cortical slices (KACZMAREK and DAVISON, 1972; L~HDESM~,KI and OJA, 1972), both differing from that associated with GABA transport. The efflux oftaurine from rat cortical slices has also been studied (KACZMAREK and DAVISON, 1972; L~HDESMXKI and OJA, 1972), and under in vivo conditions the efflux of taurine and of glycine from the surface of the cortex of intact or encephale isol6 cats was enhanced during electrocortical arousal (JASPER and KOYAMA, 1969). Although GABA levels in the cortical grey matter are not high (Table 3) the values exceed that of white matter (Human: 0.7 gmole/g, SYnNSKY, 1969. Rhesus monkey: 0.3 gmole/g, FAHN and C6TI~, 1968; 0.5 gmole/g, DEFEUDIS, DELGADO, and ROTH, 1970). Furthermore the GABA content of single Betz cells (Cat: 2,5 mM, OTSUKA, OBATA, MIYATA, and TANAKA, 1971) is higher than that of spinal motoneurones (0.9) but not as high as that of Deiters' neurones (6.3). In the motor cortex of adult monkey (Macaca mulatta) highest levels of GABA occur in the outer two layers, whereas in the visual cortex the highest level is found in layer 4 (HIRSCH and ROBINS, 1962). GABA has not been shown to be specifically associated with synaptosomes prepared from cortical tissue (RYALL, 1964; MANGAN and WHITTAKER, 1966; WHITTAKER, 1968; HEAL and IVERSEN, 1969; TACHIKI et al., 1972), although a high proportion of cortical GAD is present in these particles (DE ROBERTIS, 1968). The level of this enzyme in the cerebral cortex is moderately high (LOWE, ROBINS, and EYERMAN, 1958; ALBERS and BRADY, 1959; MOLLER and LANGEMANN, 1962), in the occipital cortex levels in layers 3 and 4a exceed those of other cortical layers (ALBERS and BRADY, 1959). Similarly, cortical levels of GABA-T are moderate, in both the occipital and motor areas the highest levels occur in layers 2 and 3 (SALVADOR and ALBERS, 1959). A number of investigations have been concerned with the specificity, kinetics, mechanism and effects of drugs on the carrier mediated uptake of GABA by homogenates or slices of cortical tissue (see Section 3.2). The subcellular distribution of labelled GABA appears to be similar to that of the endogenous amino acid (HEAL and [VERSEN, 1~)69, but see TACHIKI, et al., 1972), the principal sites of uptake by homogenates and slices being nerve terminals (IvERSEN and BLOOM, 1972; H6KFELT and LJUNGDAHL, 1971 b). Following direct injection of labelled GABA into the parietal cortex of rats, the amino acid is accumulated by stellate cells of layers II and III (HOKFELT and LJUNGDAHL, 1972a). The efflux of GABA from the surface of the cerebral cortex of the cat has been correlated with the presence of slow wave and spindle EEG activity, being considerably reduced by reticulo-cortical activation (JASPER, KHAN, and ELLIOTT, 1965 ; JASPER and KOYAMA, 1969). GABA efflux, however, is enhanced by electrical stimulation of medial brain stem structures (Cat: KOYAMA and JASPER, 1972, personal communication) ~ind a calcium-dependent release of both endogenous and labelled GABA (presumably from inhibitory synaptic terminals) from the cat visual cortex has been demonstrated to accompany cortical inhibition induced by electrical stimulation of the cortical surface or of the lateral geniculate nucleus (IVERSEN et al., 1971 ; IVERSEN, MITCHELL, HEAL, and SRINIVASAN, 1970). Both the spontaneous and evoked release of GABA from the visual cortex tended to be greater in animals pretreated with amino-oxyacetic acid (IVERSEN et al., 1971).
Amino Acid Transmitters in the Mammalian Central Nervous System 125 Neurochemical data for the participation of other neutral amino acids in cortical inhibition, for example imidazole-4-acetate and /%alanine, are not as detailed as that available for GABA (see Section 3.4). Important evidence for the transmitter function of GABA has been obtained in microelectrophoretic experiments of the effects of amino acids on the firing of single cortical neurones. Most experiments have been performed on physiologically identified pyramidal tract cells of the feline pericruciate cortex, and the findings account for earlier observations of the effects of topically or systemically administered amino acids on cortical function (see CURTIS and WATKINS, 1965). The depression of the firing of cortical neurones by GABA (Cat: KRNJEVI~ and PHILLIS, 1963; CRAWFORD and CURTIS, 1964; KRNJEVld, 1964. Rat: BISCOE, DUG- GAN, and LODGE, 1972. Rabbit: CLARKE and HILL, 1972) is associated with membrane hyperpolarization and an increased conductance (KRNJEVI~ and SCrrWARTZ, 1967 b) which, like the membrane changes accompanying inhibition at synapses activated by electrical stimulation of the cortical surface (KELLY, KRNJEVI~:, MORRIS, and YaM, 1969), appears to involve predominantly an increased chloride ion permeability (DREIVUSS, KELLY, and KRNJEVId, 1969). Since most comparisons between synaptic and GABA inhibition have hitherto been made on cortical neurones with relatively low resting potentials, further examination of the ionic mechanism of inhibition is warranted, including that of inhibitions evoked by more physiological stimuli. Nevertheless the postsynaptic action of GABA is generally accepted to closely resemble that of the inhibitory transmitter released upon the bodies of cortical pyramidal cells. Of the naturally occuring neutral amino acids, GABA is the most effective depressant of the firing of cortical neurones, glycine, e-alanine and taurine being much less active (KRNJEVI(; and PHILLIS, 1963; CRAWFORD and CURTIS, 1964; JOHNSON et al., 1970; CURTIS et al., 1971b; BIscoE et al., 1972). Furthermore the postsynaptic inhibitory action of glycine may differ from that of GABA (KZLLY and KRNJEVI~, 1969). Although electrophoreticatly administered aminooxyacetic acid did not modify the time course of either the action of similarly administered GABA, or the synaptic inhibition of cortical neurones, the effect of GABA was enhanced, and inhibition resulting from stimulation of the cortical surface or the pyramidal tract prolonged, following intravenous administration of amino-oxyacetic acid (GoTTESF~LD, KELLY, and RENAtJD, 1972). These effects were interpreted in terms of an interference with the removal of GABA after synaptic or electrophoretic release (see also SNODGRASS and IV~RSEN, 1973 b), but the selectivity of amino-oxyacetic acid in relation to other depressant amino acids was not determined (GOTTESVELD et al., 1972). Further evidence for an inhibitory transmitter role of GABA (or a GABA-like substance) has been obtained by the use of strychnine and bicuculline. The effects of these convulsants on the firing and responses of cortical neurones are complex, particularly after systemic administration. However much valuable information has been obtained from microelectrophoretic experiments, and the controversies which have arisen are perhaps mainly associated with methodological difficulties and differences of technique rather than reflecting serious conflicts in the understanding of amino acid-receptor interactions. In numerous electrophoretic experiments strychnine has been demonstrated to be a selective antagonist of the depres-
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Amino acid transmitters in the mammalian central nervous system

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