Amino acid transmitters in the mammalian central nervous system

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112 D.R. CURTIS and G.A.R. JOHNSTON: reported (LEvi and RAITERI, 1973). Various drugs inhibit GABA uptake in a relatively non-specificmanner, includingp-chloromercuriphenylsulphonate, chlorpromazine, imipramine, haloperidol, dibutyryl cyclic AMP and the protoveratrines (Rat: IVERSEN and JOHNSTON, 1971 ; GOTTESFELD and ELLIOTT, 1971 ; BEART and JOHNSTON, 1973b; HARRIS, HOPKIN, and NEAL, 1973). GABA transport appears to be dependent on pyridoxyl phosphate, and can be inhibited by relatively high concentrations of amino-oxyacetic acid (SNODGRASS and IVERSEN, 1973 b). Autoradiographic studies indicate that a major site of uptake in rat cerebral cortex is a distinct population of nerve terminals (IvERSEN and BLOOM, 1972), but this is not true of all nervous tissue (Rat: NEAL and IVERSEN, 1972). Synaptic vesicles isolated from brain bind GABA by a structurally specific, sodium dependent, process (Mouse: ROBERTS and KURIYAMA, 1968 ; KURIYAMA, ROBERTS, and KAKEFUDA, 1968) which is inhibited by imipramine (WEINSTEIN, VARON, and ROBERTS, 1971). This binding may be related to the storage of GABA in the nerve terminal. GABA Release. The release of endogenous GABA has been demonstrated in vivo into the fourth ventricle and from the surface of the cerebral cortex following appropriate stimulation (Cat: OBATA and TAKEDA, 1969; JASPER and KOYAMA, 1969; IVERSEN, MITCHELL, and SRINIVASAN, 1971). In both the spinal cord and cerebellum tetanus toxin appears to block the synaptic release of this amino acid (CURTIS, FELIX, GAME, and MCCULLOCH, 1973a). Postsynaptic Action ofGABA. GABA depresses the firing of neurones throughout the mammalian nervous system and hyperpolarization with an increased membrane conductance has been demonstrated in Deiters' nucleus, the cerebral and cerebellar cortices and the spinal cord. (Cat: OBATA, ITO, OCHI, and SATO, 1967; KRNJEVI~ and SCHWARTZ, 1967b; CURTIS et al., 1968b; BRUGGENCATE and ENGBERG, 1968. Rat: SIGGINS, OLIVER, HOFFER, and BLOOM, 1971). The reversal potentials for both synaptically- and GABA-induced hyperpolarizations are similar, and intracellular injection of ions has essentially the same effects upon both types of inhibitory hyperpolarizations. It is therefore generally accepted that GABA has transmitter-like effects at certain inhibitory synapses. GABA Antagonists'. Three series of compounds (Fig. 3) antagonise the postsynaptic effects of GABA: picrotoxin and related compounds, bicuculline and related compounds, and benzyl penicillin. < ~~N~cH3 o ? PICROTOXININ CH2CONH S CH3 BICUCULLINE o/A --" -~cooN~ BENZYI. PENICILLIN Fig. 3. Antagonists of the postsynaptic action of GABA
Amino Acid Transmitters in the Mammalian Central Nervous System 113 Picrotoxin is an equimolar mixture of picrotoxinin and picrotin (PORTER, 1967), the former being about 50 times more active than the latter as a convulsant (Mouse: RA~WELL and SHAW, 1963 ; JARBOE, PORTER, and BUCKLER, 1968). Picrotoxin reversibly, but not consistently, antagonises the action of GABA in many areas of the CNS. The structurally related convulsant tutin (FASTIER, 1971) is also a GABA antagonist in the spinal cord of the cat. Bicuculline, a convulsant phthalide isoquinoline alkaloid (Rabbit: WELCH and HENDERSON, 1934. Baboon, Rhesus monkey : MELDRUM and HORTON, 1971), is a relatively specific GABA antagonist (Cat: CURTIS et al., 1971 a). The structurally related compounds corlumine and bicucine methyl ester are similar in potency to bicuculline as convulsants and as GABA antagonists (Cat: JOHNSTON et al., 1972). Quaternisation of the heterocyclic nitrogen atom in bicuculline produces more active compounds. Bicuculline methiodide ("N-methyl-bicuculline", Rat: PONG and GRAHAM, 1972) is a more powerful convulsant than bicuculline hydrochloride when injected intracisternally. Bicuculline methochloride, which is about 100 times more soluble in water than bicuculline hydrochloride and is more active electrophoretically as a selective GABA antagonist (Cat: JOHNSTON et al., 1972), is less effective than bicuculline when administered systemically, as might be expected from its quaternary structure. Benzylpenicillin is a specific but less effective GABA antagonist than bicuculline (Frog: DAVIDOFF, 1972b. Cat: DAVIDOFF, 1972C; CURTIS, GAME, JOHNSTON, McCuLLocrt, and MACLACHLAN, 1972 b). Other substances, which like bicuculline and picrotoxinin reduce inhibitions probably mediated by GABA and are therefore possibly GABA antagonists, include shikimin (KAJIMOTO, FUJIMORI, and HIROTA, 1955. Cat: prolonged spinal inhibition, CURTIS and JOHNSTON, unpublished observation), tetramethylenedisulphotetramine (HAGEN, 1950; D.I.B. KERR, personal communication. Cat: prolonged spinal inhibition, CURTIS and JOr~NSTON, unpublished observations), diphenylamino-ethanol (Cat: cerebellar inhibition of Deiters' neurones, KEE, WLLLS, and YIM, 1971). Additionally d-tubocurarine reduces the inhibitory effects of both GABA and glycine on cerebral cortical neurones (Cat: HILL, SIMMONDS, and STRAUGHAN, 1972). 3.3. Taurine Taurine is a non-protein, sulphur containing amino acid, which is a zwitterion at neutral pH with pK values of apl~rox.. 1.5 and 8.82 at 35 ° (ALBERT, 1950; KING, 1953). In the solid state, it is in an extended conformation with a gauche relationship between the protonated amino and the sulphonate groups (OKAYA, 1966). Taurine occurs in varying concentrations throughout the nervous system, the highest level being in the lateral geniculate nucleus (Cat: GUIDOTTI, BADIANI, and PEPEU, 1972), but, unlike glycine and GABA, higher levels of taurine exist in other than CNS tissue, (GAITONDE, 1970), particularly in the heart (Rat: AWAPARA, 1956). Levels are high during the period of rapid growth of the brain, and fall as the animal matures (AGRAWAL, DAVIS, and HIMWICH, 1966). Increasing
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