Amino acid transmitters in the mammalian central nervous system

Amino Acid Transmitters in the Mammalian Central Nervous System 125
Neurochemical data for the participation of other neutral amino acids in
cortical inhibition, for example imidazole-4-acetate and /%alanine, are not as
detailed as that available for GABA (see Section 3.4).
Important evidence for the transmitter function of GABA has been obtained
in microelectrophoretic experiments of the effects of amino acids on the firing
of single cortical neurones. Most experiments have been performed on physiologically
identified pyramidal tract cells of the feline pericruciate cortex, and the
findings account for earlier observations of the effects of topically or systemically
administered amino acids on cortical function (see CURTIS and WATKINS, 1965).
The depression of the firing of cortical neurones by GABA (Cat: KRNJEVI~ and
PHILLIS, 1963; CRAWFORD and CURTIS, 1964; KRNJEVld, 1964. Rat: BISCOE, DUG-
GAN, and LODGE, 1972. Rabbit: CLARKE and HILL, 1972) is associated with
membrane hyperpolarization and an increased conductance (KRNJEVI~ and
SCrrWARTZ, 1967 b) which, like the membrane changes accompanying inhibition
at synapses activated by electrical stimulation of the cortical surface (KELLY,
KRNJEVI~:, MORRIS, and YaM, 1969), appears to involve predominantly an increased
chloride ion permeability (DREIVUSS, KELLY, and KRNJEVId, 1969). Since
most comparisons between synaptic and GABA inhibition have hitherto been
made on cortical neurones with relatively low resting potentials, further examination
of the ionic mechanism of inhibition is warranted, including that of inhibitions
evoked by more physiological stimuli. Nevertheless the postsynaptic action of
GABA is generally accepted to closely resemble that of the inhibitory transmitter
released upon the bodies of cortical pyramidal cells.
Of the naturally occuring neutral amino acids, GABA is the most effective
depressant of the firing of cortical neurones, glycine, e-alanine and taurine being
much less active (KRNJEVI(; and PHILLIS, 1963; CRAWFORD and CURTIS, 1964;
JOHNSON et al., 1970; CURTIS et al., 1971b; BIscoE et al., 1972). Furthermore
the postsynaptic inhibitory action of glycine may differ from that of GABA
(KZLLY and KRNJEVI~, 1969). Although electrophoreticatly administered aminooxyacetic
acid did not modify the time course of either the action of similarly
administered GABA, or the synaptic inhibition of cortical neurones, the effect
of GABA was enhanced, and inhibition resulting from stimulation of the cortical
surface or the pyramidal tract prolonged, following intravenous administration
of amino-oxyacetic acid (GoTTESF~LD, KELLY, and RENAtJD, 1972). These effects
were interpreted in terms of an interference with the removal of GABA after
synaptic or electrophoretic release (see also SNODGRASS and IV~RSEN, 1973 b),
but the selectivity of amino-oxyacetic acid in relation to other depressant amino
acids was not determined (GOTTESVELD et al., 1972).
Further evidence for an inhibitory transmitter role of GABA (or a GABA-like
substance) has been obtained by the use of strychnine and bicuculline. The effects
of these convulsants on the firing and responses of cortical neurones are complex,
particularly after systemic administration. However much valuable information
has been obtained from microelectrophoretic experiments, and the controversies
which have arisen are perhaps mainly associated with methodological difficulties
and differences of technique rather than reflecting serious conflicts in the understanding
of amino acid-receptor interactions. In numerous electrophoretic experiments
strychnine has been demonstrated to be a selective antagonist of the depres-