Amino acid transmitters in the mammalian central nervous system

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156 D.R. CURTIS and G. A. R. JOHNSTON : lionic neurones, motoneurones and Renshaw cells (Cat: CURTIS, PHILLIS, and WATKINS, 1959; CURTIS and WATKINS, 1960; WERMAN et al., 1966, 1968; CURTIS et al., 1968b; BRUGGENCATE and ENGBERG, 1968; RYALL and DE GROAT, 1972. Rat: BlSCOE et al., 1972. Toad: ENDO and ARAKI, 1969). In part these observations account for the effects ofintrathecal (DHAWAN, SHARMA, and SRIMAL, 1972) or systemic glycine WERMAN, DAVIDOFF, and APRISON, 1967 ; SXERN and HAD2OVI~, 1970; TAKANO and NEUMANN, 1972)and fl-alanine (MUNEOKA, 1961) on spinal reflexes. In general electrophoretic glycine was a more effective depressant of the firing of feline interneurones, and particularly of motoneurones, than GABA (CURTIS et al., 1968a, b; WERMAN et al., 1968; BRUGGENCATE and ENGBERG, 1968) whereas the amino acids were approximately equipotent when tested on Renshaw cells (CURTIS et al., 1968 a). The depression of neurone excitability by glycine is associated with a membrane hyperpolarization and conductance increase (WERMAN et al., 1968; CURTIS et al., 1968b; BRUGGENCATE and ENGBERG, 1968). These changes are rapid in both onset and offset, with prolonged ejection of glycine the hyperpolarization becomes reduced in magnitude in the presence of a sustained increase in conductance, probably because protracted activation ofglycine receptors results in altered ion concentrations in both the intra- and extracellular phases, so changing equilibrium potentials for individual ions. Intracellularly administered glycine appears not to have a hyperpolarizing effect on the motoneurone membrane (GLoBUS et al., 1968). The reversal potential for the glycine hyperpolarization of motoneurones was at a slightly more hyperpolarized level than the maximum hyperpolarization which could be achieved, and was either approximately identical to or at a slightly less hyperpolarized level than the reversal potential for short latency, direct IPSP's (WERMAN et al., 1968; CURTIS et al., 1968b). A close similarity was also demonstrated for the reversal potentials of the glycine hyperpolarization of interneurones and that of IPSP's evoked by impulses in hind limb afferents and descending fibres in the cord (BRUGGECATE and ENGBERG, 1968). Such observations would suggest that the equilibrium potentials for the ionic permeability changes induced by the amino acid and the synaptically released transmitter were identical, and hence that the changes in ion permeability were the same; the slight differences in reversal potentials would be expected from differences in the geometric distribution of membrane affected by glycine and by the transmitter in relation to the intracellular polarizing electrode. Close similarities in these two mechanisms were also indicated by a study of the effects of intracellulafly injected anions and potassium on the glycine hyperpolarization and the IPSP. In particular, synaptic membrane activated by glycine and the transmitter appear to discriminate between chloride, bromide and iodide in the same ratio (WERMAN et al., 1968). Furthermore those anions known to convert hyperpolarizing IPSP's into depolarizations--bromide, iodide, chloride, nitrite, thiocyanate, chlorate and formate (EccLES, 1966) had a similar effect on glycine hyperpolarization, whereas intracellular injection of bromate, sulphate and citrate were without effect on either type of potential (CURTIS et al., 1968 b). Thus, within the limits of the available techniques, glycine and the transmitter at certain spinal inhibitory synapses initiate the same change in the permeability of the postsynaptic membrane to chloride, and possibly also to potassium ions
Amino Acid Transmitters in the Mammalian Central Nervous System 157 (ECCLES, 1966). The types of inhibition used in these comparisons were of relatively short latency and duration, such as "direct" IPSP's evoked by impulses in group Ia muscle afferents which are readily reversed in direction by polarizing currents or ions passed from an intracellular microelectrode, and hence are generated at synapses located predominantly on the soma and proximal portion of motoneurone dendrites (EccLES, 1966; SMITH, WUERKER and FRANK, 1967; JAN- KOWSKA and ROBERTS, 1972). There is also evidence for a similar location of inhibitory terminals mediating the inhibition ofmotoneurones by volleys in groups Ib and III muscle afferents, cutaneous afferents and the recurrent inhibition ofmotoneurones (COOMBS, ECCLES, and FATT, 1955 a), although synapses mediating recurrent inhibition appear to be more distal from the soma than those of direct inhibition (BURKE, FEDINA, and LUNDBERG, 1971). On the foregoing evidence it might readily be concluded that the transmitter at" these synapses was glycine, particularly if neurochemical evidence of the presence and distribution of this amino acid is considered together with the association established with small spinal neurones in aortic occlusion experiments. However, similar changes in the membrane properties of motoneurones have been observed to result from electrophoretic administration of fl-alanine, GABA (CURTIS et al., 1968b) and 6-aminovaleric acid (BRUGGENCATE and ENGBERG, 1968). Of these substances only glycine and GABA warrant serious consideration as transmitters on neurochemical grounds, although such a function for L-~-alanine and taurine cannot be fully excluded as these depressant amino acids presumably have postsynaptic effects similar to those of glycine. One very important characteristic of these types of short latency spinal inhibition is sensitivity to strychnine. In particular "direct" and recurrent inhibition ofmotoneurones are reversibly blocked by relatively low concentrations of strychnine administered intravenously (Cat: BRADLEY, EASTON, and ECCLES, 1953; ECCLES, FATT, and KOKETSU, 1954) or electrophoretically (CURTIS, 1962), in the absence of significant modification of the activity of the appropriate inhibitory interneurones. A close analysis of the effects of strychnine on recurrent IPSP's supports previous proposals that the alkaloid probably hinders the access of transmitter to receptor sites rather than interferes with the flow of ions through the activated membrane (LARSON, 1969). Other types of inhibition of these cells are also affected, including those of spinal (COOMBS, ECCLES, and FATT, 1955b, CURTIS, 1963) and supraspinal (see CURTIS, 1969) origin. The recurrent inhibition of gamma motoneurones is also blocked by strychnine (ELLAWAY, 1971), as is also the inhibition of Renshaw cells by impulses originating in hind paw afferents and from the medullary reticular formation (BISCOE and CURTIS, 1966). It is thus very significant in establishing glycine, as a spinal transmitter that strychnine selectively and reversibly blocks the inhibitory effect of glycine (and of "glycine-like" a- and fl-amino acids) on spinal motoneurones, interneurones, Renshaw cells and autonomic neurones, but shows little or no antagonism towards the action of GABA and "GABA-like" 7- and higher ~o-amino acids (Cat: CURTIS et al., 1968b, 1971c; LARSON, 1969; DE GROAT, 1970b. Rat: BISCOE et al., 1972). Even the one apparently dissenting report indicates that the effect of glycine on spinal neurones is suppressed more completely by strychnine than is that of GABA (DAVIDOFF, APRISON, and WERMAN, 1969).
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