Amino acid transmitters in the mammalian central nervous system

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114 D.R. CURTIS and G.A.R. JOHNSTON : the plasma levels of taurine 100 fold does not significantly increase brain levels (Rat: LEVI, 1968). The rate of entry of taurine into the brain from the blood is the same in immature and mature rats (BASOS et al., 1971). Repeated administration of taurine reduces both the seizure activity and the abnormalities of cortical amino acid levels induced by cobalt in the cortex (Cat, mouse: VAN GELDER, 1972). Taurine Metabolism. Taurine is synthesised in the CNS via decarboxylation of cysteinesulphinic acid to hypotaurine and subsequent oxidation (GAITONDE, 1970). The decarboxylase activity appears to be associated with nerve endings in rat brain (AGRAWAL, DAVISON, and KACZMAREK, 1971). Taurine is degraded slowly in rat brain to isethionic acid (PECK and AWAPARA, 1967). Taurine Transport. Taurine is taken up into brain slices by at least two kinetically distinct transport systems with Km's of 5 x l0 -5 M and 1 x 10 -2 M (Rat: KACZMAREK and DAVlSON, 1972 ; LAHDESMAKI and OJA, 1972). Uptake of taurine by the low K m system is structurally specific for taurine and is inhibited by cyanide and ouabain (Cat: BATTISTIN, GRYNBAUM, and LAJTHA, 1969a. Rat: KACZMAREK and DAVISON, 1972). Taurine Release. Endogenous taurine is released from the feline cerebral cortex in vivo as a result of stimulation of the reticular formation (JASPER and KOYAMA, 1969). Exogenous taurine is released from rat brain slices under a variety of conditions (KACZMAREK and DAVISON, 1972; LAHDESMXKI and OJA, 1972). Postsynaptic Action of Taurine. Intracellular studies of the mechanism of taurine-induced depression of neuronal firing have not yet been reported, but an action similar to glycine seems very likely. Taurine Antagonists. In the feline spinal cord and medulla, strychnine, but not bicuculline, is a taurine antagonist, but in the cerebral cortex and lateral geniculate nucleus both strychnine and bicuculline block the depression of neuronal firing by taurine. (CURTIS et al., 1968a, 1971 a; CUP, T~S, DUGGAN, FELIX, JOHNSTON, and MCLENNAN, 1971 b; CURTIS and TEB~CtS, 1972). 3.4. Structurally Related Depressant Amino Acids A number of depressant amino acids structurally related to glycine, GABA and taurine occur in central nervous tissue. L-c~-Alanine. This amino acid is present in moderate amounts throughout the CNS, showing little regional variation (TALLAN, 1962; Rat: SHAW and HHNE, 1965; SI~ANK and APmSON, 1970. Cat: BATXISTIN, GRYNBAU~4, and LAJTHA, 1969b). After intraperitoneal administration L-e-alanine (11 gmole/g) raises the csntral levels of L-c~-alanine and also of glycine (Rat: RICHTER and WA1NER, 1971). This amino acid is taken up into brain slices by the "low affinity" small neutral amino acid transport system (COHEN and LmTHA, 1972; Rat: SMmt, 1967; JOHNSTON and IVERSEN, 1971; LOGAN and SNYDER, 1972). Exogenous L-e-alanine is not released from slices of rat brain or spinal cord by electrical stimulation (MITCHELL, NEAL and SRIMVASAN, 1969; HOVKIN and NEAL, 1971). The depressant effect of L-ct-alanine on the firing of feline spinal neurones, weaker than glycine but stronger than L-cystathionine and L-serine, is blocked by strychnine (CURTIS et al., 1968a). L-Serine. L-Serine and glycine are interconvertible in the CNS. In the rat, serine concentrations are lower than glycine in all areas of the CNS, other than in the telencephalon and c~rebellum
Amino Acid Transmitters in the Mammalian Central Nervous System 115 (Rat: SHAW and HEINE, 1965; SHANK and APRISON, 1970). L-Serine is also concerned with the metabolism of L-cystathionine (GAITONDE, 1970). Intraperitoneally administered glycine (13 pmole/g) raises the central levels of serine (Rat: RICHTER and WAINER, 1971).The rate of entry of serine from the blood into the brain of immature rats is 40-120 times that of mature rats (BA~oS et al., 1971). When administered electrophoretically L-serine is a weak strychnine-sensitive depressant of the firing of feline spinal neurones (CURTIS et al., 1968a). L-Serine does not influence the high affinity uptake of glycine by slices of cat and rat spinal cord (JOHNSTON and IVERSEN, 1971 ; BALCAR and JOHNSTON, 1973), and is itself taken up by a "low affinity" system (Km approx. 6 × 10-4M) into slices and homogenates of rat cord (JOHNSTON and IVERSEN, 1971 ; LOGAN and SNVDER, 1972). L-Cystathionine. The levels of L-cystathionine in the CNS vary over a wide range, with high levels in the cerebellum (Rat: SHAW and HEINE, 1965; KANDERA, LEVI, and LAJTHA, 1968) and the bovine pineal body (LABELLA, VIVIAN, and QUEEN, 1968). Spinal levels in cats (WERMAN, DAVIDOFF, and APRISON, 1966) were overestimated by a factor of ten (WERMAN, 1972). L-Cystathionine has a relatively weak, strychnine-sensitive, depressant action on the firing of feline spinal neurones (WER- MAN, DAVIDOFF, and APRISON, 1966; CURTIS et al., 1968a). When intravenously administered, it is not transported into the brain but metabolic degradation products are incorporated into brain protein (Rat: BROWN and GORDON, 1971). Hypotaurine. This sulphinic acid, a metabolic precursor of taurine, has been detected in extracts of rat brain (BERGERET and CHATAGNE, 1954). Hypotaurine depresses the firing of feline spinal neurones (CURTIS and WATKINS, 1965), and inhibits the uptake of taurine by rat brain slices (KACZ- MAREK and DAVISON, 1972). fl-Alanine. Very low levels of this amino acid occur in the CNS (TALLAN, 1962; Human: PERRY et al., 1971 a. Cat: PERRY et al., 1972. Rat: SCHENCK, 1943; YOSHINO, DEFEUDIS, and ELLIOTT, 1970). The hyperpolarization by fl-alanine of feline spinal motoneurones is similar to that of glycine (CURTIS et al., 1968b). In the feline spinal cord and lateral vestibular nucleus the depressant action of fl-alanine is antagonised by strychnine and unaffected by bicuculline, but in the thalamus and in the cerebral, cerebellar and hippocampal cortices, this action is antagonised by both alkaloids (CURTIS et al., 197l a, b). 7-Aminobutyrylchotine. This GABA derivative, present in the brain, has little or no depressant action in the cat on the firing of spinal interneurones or neurones of the cerebral cortex, but does influence the firing of Renshaw ceils in the spinal cord. These and other observations suggest that the pharmacological actions of this compound in the CNS may be related to cholinergic systems rather than to those involving GABA (JOHNSTON and CURTIS, 1972). 7-Amino-fl-hydroxybutyric Acid. While the betaine carnitine undoubtedly occurs in the brain, controversy still surrounds the role (HAYASHI, 1966), and even the presence (BAXTER, 1970; Mouse, ox: SELLER and WIECHMANN, 1969. Rat: YOSHINO, DEFEUDIS, and ELLIOTT, 1970) of y-amino-flhydroxybutyric acid in nervous tissue. It is not a substrate for GABA-T (Rat: SYTINSKY and VASILHEV, 1970; BEART and JOHNSTON, 1973a) and can be only a relatively weak substrate for the GABA uptake system in rat brain slices (IVERSE~ and JOHNSTON, 1971). The amino acid is a weaker depressant of the firing of central neurones than is GABA, and this action is antagonised by bicuculline but not by strychnine (Cat: CURTIS et al., 1971 a, b). lmidazole-4-acetic Acid. This histamine metabolite (KAHLSON and ROSENGREN, 1971) structurally resembles both GABA and fl-alanine. Following parental administration, imidazole-4-acetic acid has mixed excitant and depressant effects (Mice, rats: TUNNICLIFF, WEIN, and ROBERTS, 1972), although, on electrophoretic administration the firing of neurones in the feline spinal cord, cerebral cortex and medulla is depressed, an effect comparable in potency to GABA and suppressed by bicuculline (PHILLIS, TEBECIS, and YORK, 1968; CURTIS et al., 1971a, b; HAAS, ANDERSON, and H6SLI, 1972). Imidazole-4-acetic acid is a weak inhibitor of GABA uptake into slices of spinal cord (Cat: BALCAR and JOHNSTON, 1973), and of rat brain GAD I (SMALL, HOLTON, and ANCILL, 1970). 2,4-Diaminobutyric acid. This amino acid has been detected in brain (Ox : NAKAJIMA, WOLFGRAM and CLARK, 1967), is a weak depressant of spinal interneurones (Cat: CURTIS and WATKINS, 1960) and a comparatively strong non-competitive inhibitor of the uptake of GABA by rat brain slices (IVERSEN and JOHNSTON, 1971).
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