Amino acid transmitters in the mammalian central nervous system

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140 D.R. CURTIS and G, A. R. JOHNSTON : 4.8.3. Red Nucleus Dissected red nucleus neurones contain moderate levels of GABA (Cat: 3.5 mM, MIYATA, OBATA, TANAKA, and OTSUKA, 1970), and overall levels of other amino acids in the human nucleus are listed by PERRY et al. (1971a). L-glutamate and L-aspartate excite neurones of the nucleus (Cat: DAVIS and VAUGHAN, 1969; ALTMANN, STEINBERG, BRUGGENCATE, and SONNHOF, 1972. Baboon: parvicellular and magnocellular neurones, DAVIS and HUFFMAN, 1969), and further investigation seems warranted of inhibitory pathways projecting to this region as glycine was a more potent depressant than GABA in the baboon (DAvis and HUFFMAN, 1969), but the inhibitory actions of GABA were more pronounced than those of glycine in the cat (ALTMANN et al., 1972). 4.9. Vestibular Nuclei There is very acceptable evidence that GABA is the inhibitory transmitter released at the terminals of Purkinje cell axons in the dorsal portion of the lateral vestibular nucleus (Deiters' nucleus), although the origin of pathways which could account for the inhibitory effect of glycine upon Deiters' cells remains unknown. In the cat, axons of anterior vermal Purkinje cells terminate in Deiters' nucleus, the ventral portion of the lateral vestibular nucleus (LVN) being devoid of such afferents (WALBERG and JANSEN, 1961). The terminal portion of Purkinje axons form basket-like structures around Deiters' neurones (BRODAL, POMPEIANO, and WALBERG, 1962), the synaptic terminals are somatic and dendritic upon all types of neurone in the nucleus and contain flattened vesicles (MUGNAINI and WALBERG, 1967). 4.9.1. Neurochemistry When dissected free from freeze dried tissue, the mean GABA content of single neurones and adhering terminals from the dorsal LVN is 6.3 lamole/g, that of ventral neurones being 2.7 gmole/g, the overall level in the vestibular nuclei being 1.8 gmole/g (Cat: OTSUKA et al., 1971). Similar analyses performed 9 and 40 days after total removal of the vermis yielded mean values of 1.7 lamole/g for dorsal neurones, the levels for ventral neurones being unaltered (OTSUKA et al., 1971). The suggestion that GABA is concentrated in Purkinje terminals on Deiters' neurones gained support from estimations of the levels of GAD in the vestibular nucleus before and after cerebellar ablation (FoNNUM, STORM- MATrIISEN, and WALBERG, 1970; see also FONNUM, 1972). Using tissue samples dissected from freeze-dried material, the activity of GAD in the dorsal portion of the nucleus (16.1 + 3.4 ~tmoles CO2/h/g dry weight) exceeded that in the ventral portion by a ratio of 2.54, and was approximately three times the activity of the enzyme in white matter dorsal to the LVN, a site expected to be rich in Purkinje axons. Subsequent to destruction ofvermal Purkinje cells, the dorsal/ventral ratio of GAD activities fell to approximately 1, activity in the ventral portion
Amino Acid Transmitters in the Mammalian Central Nervous System 141 remaining unaltered and there being no major disturbance of the distributions of choline-acetyltransferase, acetylcholinesterase, lactate dehydrogenase or succinate dehydrogenase. The major proportion (approx. 60%) of GAD was found in the particulate fraction of LVN homogenates (FONNUM et al., 1970), and calculations based on these studies, and those of OTSUKA and his colleagues, suggest that the concentration of GABA within Purkinje cell terminals on Deiters' neurones is approximately 58 raM, and the GAD activity is capable of synthesizing 350mM GABA/h (Cat: FONNUM and WALBERG, 1973). Similar high levels of the amino acid and enzyme have been proposed for Purkinje terminals in the nucleus interpositus, and these values are comparable with GABA concentrations of 100-150 mM proposed for invertebrate inhibitory axon terminals (KRAVITZ and POTTER, 1965). Detailed analyses are not available for the distribution of other amino acids or their associated enzymes in the LVN. 4.9.2. Inhibition Monosynaptic inhibitory hyperpolarizations have been recorded from Deiters' neurones in response to impulses in Purkinje cell axons evoked by electrical stimulation of the anterior lobe of the cerebellum; the reversal potential of these IPSP's is more negative than the resting potential and the IPSP's are reversed to depolarizations by elevation of the intracellular chloride ion concentration (Cat: Ixo and YOSHIDA, 1966; see also ECCLES et al., 1967). Electrophoretic hydroxylamine, but not amino-oxyacetic acid, occasionally enhanced the amplitude of IPSP's without any modification of time course (OBATA et al., 1967). Electrophoretic GABA, which depresses the firing of Deiters' neurones, also hyperpolarizes the membrane, an effect associated with an increased conductance and a reversal potential similar to that of IPSP's evoked by cerebellar stimulation (Cat: OBATA et al., 1967; OBATA, TAKEDA, and SHINOZAKI, 1970; BRUGGENCATE and ENGBERG, 1971). A hyperpolarizing action has also been demonstrated for glycine, fl-alanine, c~-aminovaleric and e-aminocaproic acids, the reversal potential for hyperpolarization by glycine being indistinguishable from that by GABA (OBATA et al,, 1970; BRUGGENCATE and ENGBERG, 1971). In all studies, however, GABA has been the most potent depressant of Deiters' neurones (see also CURTIS et al., 1971 b). A clear association between inhibition by Purkinje cell impulses and GABA has been established by the effects of strychnine, picrotoxin, and bicuculline. The synaptic inhibition (Purkinje cell) of Deiters' neurones is insensitive to strychnine (Cat: Intravenous, to 0.7 mg/kg, OBATA et al., 1967. Electrophoretic, OBATA et al., 1970) but is reduced or blocked completely by picrotoxin (Cat: Intravenous, 5 10 mg/kg, OBATA et al., 1970) or bicuculline (Cat: Intravenous, 0.05-0.1 mg/kg, CURTIS, DUGGAN, and FELIX, 1970a). Stychnine reduces the inhibitory effect of glycine without modification of that of GABA (Electrophoretic, intravenous, OBATA et al., 1970. Electrophoretic, BRUGGENCATE and ENGBERG, 1971 ; CURTIS et al., 1970a). In contrast, selective antagonism of GABA but not of glycine has been demonstrated with bicuculline (CURTIS et al., 1971 b) and with a propor-
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Amino acid transmitters in the mammalian central nervous system

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