108 D.R. CURTIS and G. A. R. JOHNSTON : GLUCOSE >- 3-PHOSPHO- r: D-GLYCERATE "- I-- lb CH:zOPO } PHOSPHO co HYDROXY PYRUVATE IOO-
<strong>Am<strong>in</strong>o</strong> Acid Transmitters <strong>in</strong> <strong>the</strong> Mammalian Central Nervous System 109 Glyc<strong>in</strong>e Transport. At least two k<strong>in</strong>etically dist<strong>in</strong>ct transport <strong>system</strong>s mediate glyc<strong>in</strong>e uptake <strong>in</strong> <strong>the</strong> CNS : a "low aff<strong>in</strong>ity" <strong>system</strong> (K<strong>in</strong> approx. 10- 4 M), which is shared by o<strong>the</strong>r small neutral am<strong>in</strong>o <strong>acid</strong>s and is found <strong>in</strong> all areas of <strong>the</strong> CNS (Rat: SMITH, 1967. Mouse: BLASBERG, 1968), and a "high aff<strong>in</strong>ity" <strong>system</strong> (K m approx. 10 s M), which is specific for glyc<strong>in</strong>e, conf<strong>in</strong>ed to <strong>the</strong> sp<strong>in</strong>al cord, pons and medulla, and shows an absolute dependence on external sodium ions (Rat: NEAL, 1971; JOHNSTON and IVERSEN, 1971; LOGAN and SNYDER, 1972; BENNETT, LOGAN, and SNYDER, 1972. Cat: BALCAR and JOHNSTON, 1973). There is evidence from subcellular fractionation and autoradiographic studies to support a predom<strong>in</strong>antly presynaptic location for <strong>the</strong> high aff<strong>in</strong>ity specific glyc<strong>in</strong>e uptake <strong>system</strong>, though glial components may also be important (Rat: IVERSEN and JOHN- STON, 1971; MATUS and DENNISON, 1972; ARREGUI, LOGAN, BENNETT, and SNYDER, 1972; HOKFELT and LJUNGDAHL, 1972C). A variety of <strong>central</strong>ly-active drugs <strong>in</strong>hibit <strong>the</strong> high aff<strong>in</strong>ity specific glyc<strong>in</strong>e uptake <strong>system</strong> <strong>in</strong>clud<strong>in</strong>g chlorpromaz<strong>in</strong>e, imipram<strong>in</strong>e and haloperidol (Rat: JOHNSTON and IVERSEN, 1971). p-Chloromercuriphenylsulphonate <strong>in</strong>hibits glyc<strong>in</strong>e uptake <strong>in</strong>to slices of cat sp<strong>in</strong>al cord (BALCAR and JOHNSTON, 1973) and, when adm<strong>in</strong>istered microelectrophoretically, potentiates <strong>the</strong> depressant action of glyc<strong>in</strong>e on <strong>the</strong> fir<strong>in</strong>g of cat sp<strong>in</strong>al neurones (CURTIS et al., 1970b). Glyc<strong>in</strong>e Release. Evoked release of exogenous glyc<strong>in</strong>e has been demonstrated <strong>in</strong> vivo from cat sp<strong>in</strong>al cord (JORDAN and WEBSTER, 1971), and <strong>in</strong> vitro from slices of rat sp<strong>in</strong>al cord (HoPKIN and NEAL, 1971 ; HAMMERSTAD, MURRAY, and CUTLER, 1971) and isolated amphibian cords (APRISON, 1970 ; ROBERTS and MIT- CHELL, 1972). In <strong>the</strong> sp<strong>in</strong>al cord tetanus tox<strong>in</strong> blocks glyc<strong>in</strong>e mediated <strong>in</strong>hibition probably by reduc<strong>in</strong>g <strong>the</strong> release of transmitter (Section 4.12.3.1). Postsynaptic Action of Glyc<strong>in</strong>e. Intracellular studies of <strong>the</strong> mechanism of <strong>the</strong> depression by glyc<strong>in</strong>e of <strong>the</strong> fir<strong>in</strong>g of neurones <strong>in</strong> <strong>the</strong> sp<strong>in</strong>al cord, medulla and cerebral cortex show that glyc<strong>in</strong>e hyperpolarises <strong>the</strong>se neurones and <strong>in</strong>creases <strong>the</strong> membrane conductance (Cat: WERMAN, DAVIDOFF, and APRISON, 1968; CURTIS, HOSLI, JOHNSTON, and JOHNSTON, 1968 b; BRUGGENCATE and ENGBERG, 1968, 1971 ; KELLY and KRNSEVId, 1969; HOSLI and HAAS, 1972). The ionic basis of <strong>the</strong> effects of glyc<strong>in</strong>e on sp<strong>in</strong>al and Deiters' neurones cannot be dist<strong>in</strong>guished from synaptically-<strong>in</strong>duced <strong>in</strong>hibition by measurements of reversal potentials and <strong>the</strong> effects of <strong>in</strong>tracellular <strong>in</strong>jection of a series of anions and cations. Glyc<strong>in</strong>e Antagonists. A variety of compounds (Fig. 2) selectively antagonise <strong>the</strong> depressant action of glyc<strong>in</strong>e on neurones (Section 4.12.3.1.). Strychn<strong>in</strong>e is <strong>the</strong> most potent and <strong>the</strong> most widely <strong>in</strong>vestigated of <strong>the</strong>se compounds; o<strong>the</strong>rs <strong>in</strong>clude <strong>the</strong> alkaloids bruc<strong>in</strong>e, dendrob<strong>in</strong>e, diabol<strong>in</strong>e, gelsem<strong>in</strong>e, laudanos<strong>in</strong>e, morph<strong>in</strong>e and <strong>the</strong>ba<strong>in</strong>e, and <strong>the</strong> syn<strong>the</strong>tic compounds N,N-dimethylmuscimol, levorphan, N-methylbicuculle<strong>in</strong>e, and 4-phenyl-4-formyl-N-methylpiperid<strong>in</strong>e (Cat: CURTIS, H6SLI, and JOHNSTON, 1968 a; CURTIS and DUGGAN, 1969 ; CURTIS, DUGGAN, FELIX, and JOHNSTON, 1971a; JOHNSTON, BEART, CURTIS, GAME, MCCULLOCH, and MACLACHLAN, 1972; CURTIS and JOHNSTON, unpublished observations). Strychn<strong>in</strong>e also antagonises <strong>the</strong> depressant actions on sp<strong>in</strong>al neurones of ~- and fl-alan<strong>in</strong>e, cystathion<strong>in</strong>e, ser<strong>in</strong>e and taur<strong>in</strong>e, which on this basis have been called "glyc<strong>in</strong>e-like" am<strong>in</strong>o <strong>acid</strong>s, but does not <strong>in</strong>fluence <strong>the</strong> actions of