Amino acid transmitters in the mammalian central nervous system

Amino Acid Transmitters in the Mammalian Central Nervous System 129
The distribution of GAD also suggests that GABA could be a transmitter
within the cerebellar cortex and nuclei. Such a proposal gains support from
pharmacological evidence cited below, and observations that [3H]-GABA, after
direct injection into the cerebellum (Rat: HOKFELT and LJUNGDAHL, 1972a) is
accumulated in stellate cells, basket cell axons and terminals, and possibly also
by Golgi cells, all of inhibitory function (ECCLES, ITO, and SZ~NTAGOTHAI, 1967).
Similarly, superficially located stellate cells accumulate [3H]-GABA after injection
into the lateral ventricle (Rat: SCHON and IVERSEN, 1972), no such specific localization
could be shown for [3H]-glycine. The uptake of GABA by rat cerebellar
cortical tissue is approximately 50% of that by cerebral cortical tissue (H6KVELT,
JONSSON, and LJUNGDAHL, 1970; IVERSEN and JOHNSTON, 1971). Labelled GABA
is also accumulated by neurones of cultured rat cerebellar tissue, uptake by
glia, granule cells and macrophages being minimal (SOTELO, PRIVAT, and DRIAN,
1972).
Of the other amino acids present in the cerebellum (Table 5), glycine and
~-alanine levels are low, whereas those of taurine are high: the intracerebellar
distribution of this amino acid is unknown. Only a low affinity uptake process
for glycine has been found in cerebellar tissue (Rat: JOHNSTON and IVERSEN,
1971).
The firing of Purkinje cells is readily depressed by electrophoretically administered
glycine, GABA and related amino acids including fl-alanine and taurine
(Cat: KAWAMURA and PROVINI, 1970 ; CURTIS et al., 1971 b). Of these substances
GABA was the most effective, and hyperpolarizes and increases the membrane
conductance of Purkinje cells (Rat: SIGGINS et al., 1971. Frog: WOODWARD,
HOVVER, SIGGINS, and OLIVER, 1971). It is thus highly significant to the transmitter
role of GABA that the inhibition of Purkinje cells which follows excitation
of cerebellar basket (and stellate cells) is not affected by strychnine (Cat: Intravenous,
ANDERSEN, ECCLES, LOYNING, and VOORHOEVE, 1963; CRAWFORD et al.,
1963; BISTI, IOSIF, MARCHESI, and STRATA, 1971. Electrophoretic, CURTIS and
FELIX, 1971. Also frog: WOODWARD et al., 1971), an alkaloid which does not
influence the inhibitory effect of GABA (CURTIS, et al., 1971b) but is blocked
by bicuculline (CURTIS and FELIX, 1971 ; BISTI et al., 1971), bicuculline methochloride
(CURTIS and JOHNSTON, unpublished observations) or relatively large doses
of picrotoxinin (Bisa~i et al., 1971). Furthermore the Golgi cell inhibition of
cerebellar granule cells is not influenced by strychnine (intravenous) but is reduced
by bicuculline or picrotoxinin (BISTI et al., 1971). Basket cell inhibition of Purkinje
cells is also suppressed by tetanus toxin injected into the cerebellar folium, but
as the cells retain sensitivity to electrophoretic GABA the toxin probably blocks
synaptic release of the amino acid rather than its postsynaptic action (CURTIS,
FELIX, GAME, and McCULLOCH, 1973 a).
In the absence of evidence for strychnine-sensitive inhibition in the cerebellar
cortex, the role of glycine as an inhibitory transmitter is doubtful. Furthermore,
although direct tests with taurine have not been carried out, the suppression
of the depressant effect of fl-alanine on Purkinje cells by both bicuculline and
strychnine (CURTIS et al., 1971b) probably indicates that taurine is unlikely to
function as an inhibitory transmitter of bicuculline-sensitive cerebellar inhibition.
Thus, although these studies have been mainly carried out on the cerebellar