Amino acid transmitters in the mammalian central nervous system

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146 D.R. CURTIS and G. A. R. JOHNSTON : SCHWARTZ, 1967, 1968), the effect of D-glutamate being somewhat weaker (GALINDO et al., 1967). Although both the excitatory actions of L-glutamate, L-aspartate and the synaptic firing of cuneate neurones were reduced by 1-hydroxy-3-aminopyrrolidone-2, supporting an excitatory transmitter function for the amino acid (Cat: DAVIES and WATKINS, 1973), the specificity of the antagonist towards other excitants of these neurones has not been determined. When administered topically to these nuclei L-aspartate (10-2 M) was apparently without effect whereas, L-glutamate (10- 4-10 2 M) depolarized terminals of afferent fibres (Rat: DAVIDSON and SOVTHWICK, 1971). Since this effect was not observed after the administration of sufficient picrotoxin to suppress the depolarization of terminals by conditioning volleys in afferent fibres, the depolarization of by L-glutamate has been considered to be unrelated to "presynaptic" inhibition in the cuneate nucleus (DAVIDSON and SOUTHWICK, 1971). 4.11.2. Inhibition Although the levels of individual amino acids in the gracile and cuneate nuclei have not been determined, both glycine and GABA have been considered as possible inhibitory transmitters. When administered electrophoretically these amino acids depress the activity of cuneate neurones; in general glycine is as effective as GABA although proprioceptive cells appear more sensitive to the latter amino acid (Cat: GALINOO et al., 1967). The effect ofglycine can be blocked by strychnine, that of GABA by picrotoxin (Cat: GALINOO, 1969) or bicuculline (Cat: KELLY and RENAUD, 1971). A number of studies have been concerned with the effects of amino acids on the excitability of cuneate presynaptic terminals, particularly in relation to the possible role of GABA in "presynaptic" inhibition. Although both glycine and GABA (electrophoretic) have been shown to diminish the excitability of the terminals of primary afferent fibres within the cuneate nucleus (GALINDO, 1969), the effect of GABA being blocked by electrophoretic picrotoxin, most experiments have involved topical administration of amino acid solutions. Under these conditions glycine (10- 2 M) reduced (Rat: DAVIDSON and SOUTHWICK, 1971), whereas GABA (10 -4 10 1M) enhanced presynaptic excitability (Cat: GALINDO, 1969. Rat: DAVIDSON and SOUTHWICK, 1971). This effect of GABA was blocked by picrotoxin (GALINDO, t969); alternatively topical GABA blocked the suppression by picrotoxin of primary afferent depolarization (PAD) induced by afferent volleys (DAvIDSON and SOUTHWlCK, 1971). Both short (20 msec) and long (about 200 msec) duration postsynaptic inhibition, and prolonged "presynaptic" inhibition have been proposed to account for the depression of transmission through the cuneate nucleus which follows cutaneous afferent volleys (ANDERSEN, ECCLES, OSHIMA, and SCHMIDT, 1964; ANOERSEN, ETr~OLM, and GORDON, 1970). "Presynaptic" inhibition has frequently been assessed by the presence of afferent terminal depolarization, and the involvement of GABA in these inhibitory processes is suggested by the following findings: semicarbazide lowered central GABA levels and reduced afferent terminal depolarization (Cat: BANNA and JABBUR, 1971); afferent
Amino Acid Transmitters in the Mammalian Central Nervous System 147 terminal depolarization was reduced by picrotoxin (Cat: BANNA and JABBUR, 1969. Rat: DAVIDSON and REISINE, 1971) and bicuculline (DAvIDSON and REISINE, 1971. Cat: BANNA, NACCACHE, and JABBUR, 1972); the inhibition of the firing of cuneate neurones by a prior cutaneous volley was blocked by picrotoxin (Cat: BOYD, MERITT and GARDNER, 1966; BANNA and JABBUR, 1969) and bicuculline (Cat: KELLY and RENAUD, 1971); bicuculline also blocked the inhibition of cuneate neurones by volleys in the pyramidal tract (KELLY and RENAUD, 1971). Although strychnine has been reported to diminish short latency inhibition in the cuneate nucleus (BOYD et al., 1966; BANNA and JABBUR, 1969) no clear evidence has been provided for a glycine-releasing inhibitory pathway terminating in this nucleus. The consensus of opinion seems to be that intra-nuclear inhibitory interneurones release GABA as a hyperpolarizing inhibitory transmitter upon cuneate relay neurones, and that GABA possibly also depolarizes the terminals of afferent fibres within the nucleus, an effect which will be discussed in more detail in the next section. 4.12. Spinal Cord The considerable body of information concerned with amino acid transmitters in the cord is largely the consequence of the relative ease with which this region can be studied chemically, physiologically and pharmacologically. Most investigations have been concerned with lumbar segments of the cat. 4.12.1. Neurochemistry Overall amino acid levels are of value only for comparison with other regions of the nervous system, and more useful information relative to spinal mechanisms has been derived from analyses of intraspinal amino acid distributions. The major observations are summarized for lumbar segments of the cat in Table 8, limited but similar studies have been made on other mammals (APRISON et al., 1969; SHANK and APRISON, 1970; DUGGAN and JOHNSTON, 1970b). Some of the discrepancies between figures reported by different groups may be associated with different methods of amino acid extraction and estimation. The distribution of enzymes associated with amino acid metabolism is given in Table 9. Table 8 also includes figures for peripheral nerves (see also MARKS, DATTA, and LAJTHA, 1970), these levels may represent amino acids required for metabolic purposes, the relatively high levels within dorsal root ganglia possibly being associated with protein synthesis by cell bodies. It should also be recalled that DALE (t935) anticipated an association between the transmitter of axon-reflex vasodilation and that at central synapses of the same afferent fibres. One useful technique applicable to the cord is the analysis of alterations of amino acids after selective lesions of neurones or pathways. Hindlimb rigidity can be produced in the cat by temporary occlusion of the thoracic aorta which results in a loss of small neurones in the central portion of the lumbar grey matter, involving dorsal and ventral grey, with little destruction of motoneurones
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Amino acid transmitters in the mammalian central nervous system

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