Amino acid transmitters in the mammalian central nervous system

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126 D.R. CURTIS and G.A.R. JOHNSTON : sion of feline cortical neurones by glycine (CURTIS et al., 1968 a, 1971 b; JOHNSON et al., 1970), fl-alanine and taurine (CURTIS et al., 1968a, 1971b), the action of GABA being relatively insensitive. The same high degree of selectivity appears not to occur when rat cortical neurones were studied (BISCOE et al., 1972). Furthermore the inhibition of the firing of pyramidal tract cells in the cat by local cortical stimulation (KRNJEVI~;, RANDIC and STRAUGHAN, 1966; CRAWFORD, CURTIS, VOORHOEVE, and WILSON, 1963), by recurrent volleys in the pyramidal tract (CRAWFORD et al., 1963 ; BISCOE and CURTIS, 1967), by stimulation of thalamic nuclei (KRNJEVIC; et al., 1966), and by direct chemical stimulation of intracortical interneurones (BISCOE and CURTIS, 1967) was not blocked by strychnine. In contrast, electrophoretically administered bicuculline selectively reduced the inhibitory effect of GABA and some related amino acids (fl-alanine, taurine and imidazole acetic acid) on cortical neurones of the cat (CURTIS et al., 1971 b; see also STRAUGHAN, NEAL, SIMMONDS, COLLINS, and HILL, 1971). Similar results have been observed using bicuculline methochloride (CURTIS, GAME, JOHN- SXON, and MCCULLOCH, unpublished observations). The same degree of selectivity has not been demonstrated in the rat cortex (BISCOE et al., 1972) where in a high proportion of tests bicuculline reduced the effects of both glycine and GABA. These observations are of considerable relevance to the reduction by bicuculline of the synaptic inhibition of pyramidal tract neurones by recurrent volleys, direct cortical electrical stimulation or chemical excitation of intracortical neurones (Cat: CURTIS and FELIX, 1971). Additionally, antagonism of the inhibitory effects of fl-alanine and taurine on cortical neurones by both strychnine and bicuculline probably excludes either amino acid as a transmitter of inhibitory synapses selectively blocked by bicuculline. Picrotoxin has also been reported to reduce the inhibition of cortical neurones in the cat by GABA (HILL, NIMMONDS, and STRAUGHAN, 1972b), and to reduce the effects of both GABA and glycine in the rat cortex (BISCOE et al., f972). Further investigation is warranted since the recurrent inhibition of pyramidal cells in the cat has been reported to be diminished by relatively low doses (0.1- 0.3 mg/kg, BROOKS and ASANUMA, 1965), but inhibition evoked by direct cortical stimulation appeared insensitive (0.6-2 mg/kg, KRNJEVI{~ et al., 1966). This latter inhibition was also apparently not modified by tetanus toxin (KRNJEVI~ et al., 1966), although abolition of the recurrent and transcallosal inhibition of pericruciate neurones (BROOKS and ASANUMA, 1965) suggests that the effects of tetanus toxin may be similar to those found in the cerebellar cortex (CURTIS et al., 1973 a). Penicillin has also been demonstrated to antagonize the inhibitory effect of GABA on cortical neurones, an action which may account for the epileptogenic activity of this compound (CURTIS et al., 1972b). As a consequence of these studies, a proportion of stellate cells in the cerebral cortex may be considered inhibitory in nature, releasing GABA at axosomatic synapses on pyramidal cells (see CURTIS and FELIX, 1971). Further studies are required to ascertain the location of the interneurones activated by volleys in particular inhibitory pathways, and to determine the significance of the inhibitory control by this amino acid in the functioning of pyramidal and stellate cells in various cortical areas. The importance of glycine as a cortical transmitter may be minimal, the effects of strychnine on cortical activity (AJMONE-MARSAN,
Amino Acid Transmitters in the Mammalian Central Nervous System 127 1969) probably not being associated with a specific action at glycinergic synapses (see CURTIS et al., 1971c). 4.2. Cerebellum 4.2.1. Excitation Although aspartate and glutamate levels are relatively high in the cerebellum (Table 4), the intracerebellar distributions of these amino acids have not been determined, apart from the estimation of glutamate in the cerebellar cortex (Cat: 10.8 ~tmole/g, JOHNSON and APRISON, 1971). Table 4. Cerebellar excitant amino acids (gmole/g, *Biopsy) Animal Aspartate Glutamate Reference Human 2.3 9.6 PERRY et al. (1971 a) 0.8* 7.2* PERRY et al. (1971 b) Cat 2.9 12.6 BATTISTIN et al. (1969) 10.8 JOHNSON and APRISON, 1971 1.8 * 8.5 * PERRY et al. (1972) Rat 2.2 8.4 SHAW and HEINE (1965) 2.0 10.3 KANDERA et al. (1968) 2.0 9.7 SHANK and APRISON (1970) Purkinje, basket and granule cells, and cells of the intracerebellar nuclei are excited by glutamate and DL-homocysteate (CRAWFORD, CURTIS, VOORHOEVE, and WILSON, 1966 ; CHAPMAN and MCCANCE, 1967; MCCANCE and PHILLIS, 1968 ; KAWAMtJRA and PROVINI, 1970), and the sensitivity of developing Purkinje cells to glutamate precedes the presence of dendritic synapses (WOODWARD, HOFFER, SIGGtNS, and BLOOM, 1971). Doubt has recently been cast on the identity of ergothioneine as the "cerebellar excitatory factor"(BRIGGS, 1972); when administered electrophoretically ergothioneine did not excite cerebellar neurones in the cat (CRAWFORD et al., 1966). 4.2.2. Inhibition Although the overall levels of GABA in the cerebellum are not high (Table 5), the highest values of both the amino acid and GAD occur in the Purkinje cell layer (Rabbit: KURIYAMA, HABER, SISKEN, and ROBERTS, 1966. Monkey and rat: HIRSCH and ROBINS, 1962; see also LOWE et al., 1958; ALBERS and BRADY, 1959). The GABA-T content of the molecular layer is double that of the granular layer (Monkey: SALVADOR and ALBERS, 1959). In the cat particularly high levels of GABA are associated with both Purkinje cells (5.5 + 1.1 gmole/g, cerebellar
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Amino acid transmitters in the mammalian central nervous system

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