Amino acid transmitters in the mammalian central nervous system

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128 D.R. CURTIS and G. A. R. JOHNSTON : Table 5. Cerebellar depressant amino acids (p.mole/g, *Biopsy) Cerebellum Cortex (not pure grey) Vermal cortex Human 3.0 0.9 GJESSING and TORViCK (1966) Human 2.3 2.1 3.3 1.7 0.09 PERRY et al. (1971 a) Human 0.8* 0.5* 2.5* 0.7* 3.2* PERRY et al. (1971 b) Human 1.7 BOEHME et al. (1973) Cat 1.5 1.5 3.1 0.9 0.2 BATTISTIN et al. (1969) Cat 0.8* 0.5* 2.9* 0.3* 0.2* PF, RRV et al. (1972) Cat 0.8 APRISON, SHANK, and DAVlDOFF (I969) Rat 1.6 1.0 4.9 0.9 0.2 SHAW and HEINE (1965) Rat 1.5 0.6 5.6 0.6 0.3 KANDERA et al. (1968) Rat 1.6 0.6 6.2 0.6 SHANK and APRISON (1970) Mouse 2.2 2.2 0.8 StatMADA et al. (1972) Rhesus 2.0 FAHN and C6T~ (1968) monkey Baboon 2.1 OKADA et al. (1971) Rat 3.0 OKADA et al. (1971) Rabbit 1.8 OKADA et al. (1971) Guinea pig 2.5 OKADA et al. (1971) Mouse 2.5 2.6 1.3 SHIMADA et al. (1972) cortex 1.0+0.1) and cells of intracerebellar nuclei (8.0+_1.1, nuclei 1.8+0.2; OTSUKA et al., 1971). Since the relatively high levels of GAD in the rat cerebellar cortex (46.8 + 3.6 gmole/h/g dry weight) and nucleus interpositus (151.8_+20.5) are not significantly reduced by transection of the peduncles, GAD activity is largely associated with neurones intrinsic to the cerebellum (FONNUM, 1972). Furthermore the enzyme seems roughly evenly distributed between synaptic endings and other cell components (FONNUM, 1972). Recent calculations, based on amino acid and enzyme measurements, subcellular fractionation and quantitative morphological analyses, suggest that the concentration of GABA in Purkinje cell terminals in the nucleus interpositus is 86 138mM, the activity of GAD permitting the synthesis of GABA at a maximum rate of 613 980 mM/hr (Cat: FONNUM and WALBERG, 1973). There is very strong evidence that the Purkinje cells, which are inhibitory in function, release GABA as a transmitter at terminals in the lateral vestibular nucleus (see Section 4.9). Impulses in Purkinje cell axons also inhibit monosynaptically neurones ofintracerebellar nuclei (ITO, YOSHIDA, OBATA, KAWAI, and UDO, 1970). These nuclei lie close to the roof of the fourth ventricle and, in cats pretreated with amino-oxyacetic acid, electrical stimulation of the cerebellar cortex enhances the spontaneous efflux of GABA into this ventricle by a factor of approximately three (OBATA and TAKEDA, 1969). Some success has also been achieved in detecting the release of GABA into intracerebellar nuclei by means of a push-pull cannula (OBATA, 1972 b).
Amino Acid Transmitters in the Mammalian Central Nervous System 129 The distribution of GAD also suggests that GABA could be a transmitter within the cerebellar cortex and nuclei. Such a proposal gains support from pharmacological evidence cited below, and observations that [3H]-GABA, after direct injection into the cerebellum (Rat: HOKFELT and LJUNGDAHL, 1972a) is accumulated in stellate cells, basket cell axons and terminals, and possibly also by Golgi cells, all of inhibitory function (ECCLES, ITO, and SZ~NTAGOTHAI, 1967). Similarly, superficially located stellate cells accumulate [3H]-GABA after injection into the lateral ventricle (Rat: SCHON and IVERSEN, 1972), no such specific localization could be shown for [3H]-glycine. The uptake of GABA by rat cerebellar cortical tissue is approximately 50% of that by cerebral cortical tissue (H6KVELT, JONSSON, and LJUNGDAHL, 1970; IVERSEN and JOHNSTON, 1971). Labelled GABA is also accumulated by neurones of cultured rat cerebellar tissue, uptake by glia, granule cells and macrophages being minimal (SOTELO, PRIVAT, and DRIAN, 1972). Of the other amino acids present in the cerebellum (Table 5), glycine and ~-alanine levels are low, whereas those of taurine are high: the intracerebellar distribution of this amino acid is unknown. Only a low affinity uptake process for glycine has been found in cerebellar tissue (Rat: JOHNSTON and IVERSEN, 1971). The firing of Purkinje cells is readily depressed by electrophoretically administered glycine, GABA and related amino acids including fl-alanine and taurine (Cat: KAWAMURA and PROVINI, 1970 ; CURTIS et al., 1971 b). Of these substances GABA was the most effective, and hyperpolarizes and increases the membrane conductance of Purkinje cells (Rat: SIGGINS et al., 1971. Frog: WOODWARD, HOVVER, SIGGINS, and OLIVER, 1971). It is thus highly significant to the transmitter role of GABA that the inhibition of Purkinje cells which follows excitation of cerebellar basket (and stellate cells) is not affected by strychnine (Cat: Intravenous, ANDERSEN, ECCLES, LOYNING, and VOORHOEVE, 1963; CRAWFORD et al., 1963; BISTI, IOSIF, MARCHESI, and STRATA, 1971. Electrophoretic, CURTIS and FELIX, 1971. Also frog: WOODWARD et al., 1971), an alkaloid which does not influence the inhibitory effect of GABA (CURTIS, et al., 1971b) but is blocked by bicuculline (CURTIS and FELIX, 1971 ; BISTI et al., 1971), bicuculline methochloride (CURTIS and JOHNSTON, unpublished observations) or relatively large doses of picrotoxinin (Bisa~i et al., 1971). Furthermore the Golgi cell inhibition of cerebellar granule cells is not influenced by strychnine (intravenous) but is reduced by bicuculline or picrotoxinin (BISTI et al., 1971). Basket cell inhibition of Purkinje cells is also suppressed by tetanus toxin injected into the cerebellar folium, but as the cells retain sensitivity to electrophoretic GABA the toxin probably blocks synaptic release of the amino acid rather than its postsynaptic action (CURTIS, FELIX, GAME, and McCULLOCH, 1973 a). In the absence of evidence for strychnine-sensitive inhibition in the cerebellar cortex, the role of glycine as an inhibitory transmitter is doubtful. Furthermore, although direct tests with taurine have not been carried out, the suppression of the depressant effect of fl-alanine on Purkinje cells by both bicuculline and strychnine (CURTIS et al., 1971b) probably indicates that taurine is unlikely to function as an inhibitory transmitter of bicuculline-sensitive cerebellar inhibition. Thus, although these studies have been mainly carried out on the cerebellar
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Amino acid transmitters in the mammalian central nervous system

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