Amino acid transmitters in the mammalian central nervous system

160 D.R. CURTIS and G.A.R. JortmsToY :
(ECCLES et al., 1963; KELLERTH and SZUMSKI, 1966 ; SCHMIDT, 1971), bicuculline
(CURTIS et al., 1971a; HUFEMAN and MCFADIN, 1972) and penicillin (DAVIDOEF,
1972C).
Prolonged spinal inhibition has been held to be essentially entirely presynaptic
in nature, depolarization at axo-axonic synapses on the terminals of primary
afferent fibres being responsible for a reduced release of excitatory transmitter
and hence a diminished effectiveness of excitatory volleys (SCHMIDT, 1971). Primary
afferent depolarization (PAD), detected by direct intrafibre recording,
measurement of fibre and terminal excitability or the recording of dorsal root
potentials and reflexes, is thus considered a primary event, generated at axo-axonic
synapses. The participation of GABA in this process is suggested by the depolarization
of afferent terminals demonstrated in amphibian spinal cord preparations
(SCHMIDT, 1963; TEBECIS and PHILLIS, 1969; DAVIDOEE, 1972a; BARKER and
N1COLL, 1973), an effect which is dependent on sodium ions, unaffected by tetrodotoxin
(BARKER and NICOLL, 1973), and like PAD is blocked by picrotoxinin,
bicuculline and penicillin (ScHMIDT, 1971 ; DAVIDOFE, 1972 a, b; DAVIDOEF, SILVEY,
KOBETZ and SPIRA, 1972; BARKER and NICOLL, 1973). Such direct evidence for
terminal depolarization by GABA has not been obtained in the cat, in fact
electrophoretic GABA depressed terminal excitability (CURXlS and RYALL,
1966b). Nevertheless picrotoxinin, bicuculline and penicillin reduce both PAD
and the inhibitory effect on reflexes of incoming volleys (ScHMIDT, 1971 ; CURTIS
et al., 1971a; LEVY and ANDERSON, 1972; DAVIDOEF, 1972c). Additionally,
administration of semicarbazide to acute spinal cats, which reduces spinal GABA
levels, suppresses dorsal root potentials and reflexes, and "presynaptic" inhibition
(BELL and ANDERSON, 1972).
On the other hand prolonged inhibition is considered to be postsynaptic in
nature, at synapses on dendrites so distant from the soma of motoneurones
that changes in membrane potential and conductance are not readily detected
by an intracellular microelectrode (GRANIT, 1968; KELLERTH, 1968). Evidence
has been provided of inhibitory hyperpolarizations which are reversed by intracellular
chloride ion injection and which are reduced by picrotoxin but not by
strychnine (KELLERTH, 1968; COOK and CANGIANO, 1972). The participation of
GABA as an inhibitory transmitter at such synapses would be entirely consistent
with its inhibitory effect when administered electrophoretically near spinal neutones,
and for the reduction of this synaptic inhibition by bicuculline. Furthermore,
elevation of the extracellular potassium concentration as a consequence
of prolonged activation of GABA receptors could account for the depolarization
of neighbouring synaptic terminals and hence for PAD (see CURTIS et al., 1971a).
Increases in extracellular po'tassium levels have been demonstrated in spinal tissue
to follow afferent volleys which produce "presynaptic" inhibition (Cat: SOMJEN,
1970; KRNJEVIC and MORRIS, 1972. Rat: VYKLICK~(, SYKOVA I(l~I~, and UJEC,
1972), and the depolarization would be reduced by GABA antagonists and by
substances interfering with GABA release. The only observation inconsistent
with this explanation of PAD is the apparent dependence on sodium ions of
the depolarization of amphibian spinal afferent terminals by GABA (BARKER
and NICOLL, 1973), and further investigation is necessary oflhe ionic mechanism
of PAD in mammals.