Amino acid transmitters in the mammalian central nervous system

116 D.R. CURTIS and G. A. R. JOHNSTON :
Proline. This cyclic amino acid is present in brain (Human, cat: PERRY et al., 1971 a, b, 1972)
and is a weak strychnine-sensitive depressant of cat spinal interneurones. It is taken up into rat
brain slices by a high affinity system.
3.5. L-Aspartate
L-Aspartate, like its higher homologue L-glutamate, is an optically active acidic
amino acid, with three ionizable groups (pK's of 2.05, 3.87 and 10.00 at 25°:
SIMMS, 1928), which can associate via intermolecular hydrogen bonds, both in
the solid state (DERISSEN, ENDEMAN, and PEERDEMAN, 1968) and in aqueous solution
(GLAGOI.EVA, 1967).
The central levels of L-aspartate vary from region to region, but only within
the feline spinal cord have the levels been correlated with a possible function
as a transmitter of excitatory interneurones (DAVIDOFF, GRAHAM, SHANK, WER-
MAN, and APRISON, 1967).
When systemically administered to immature animals, L-aspartate produces
degeneration of cells in the retina and hypothalamus (Mouse: OLNEY, HO and
RHEE, 1971) and seizures (Rat: JOHNSTON, 1973). Intraventricular administration
to mature mice also results in seizures (CRAWFORD, 1963).
L-Aspartate Metabolism. The metabolism of L-aspartate in the CNS resembles
that of L-glutamate in being concerned with a variety of compartments. Exogenous
L-aspartate rapidly enters the "small" L-glutamate pool where it is metabolised
via the tricarboxylic acid cycle to L-glutamine, and does not equilibrate
with a major portion of the endogenous L-aspartate. L-Aspartate transaminase,
which catalyses the reversible transamination between L-aspartate and L-glutamate,
and their corresponding oxo-acids oxalacetate and e-oxoglutarate, is present
in two forms in brain differing in location and kinetic properties: neither form
appears to be associated with nerve endings (Guinea pig, rat: FONNUM, 1968).
High concentrations of N-acetyl-L-aspartate occur in the brain but the function
of this amino acid derivative remains obscure (NADLER and COOPER, 1972).
L-Aspartate Transport. Slices and homogenates of rat brain and cat spinal
cord transport L-aspartate by the same "high" and "low" affinity systems that
transport L-glutamate (COHEN and LAJTHA, 1972; WOFSEY, KUHAR, and SNYDER,
1971 ; LOGAN and SNYDER, 1972; BALCAR and JOHNSTON, 1972a, b, 1973).
L-Aspartate Release. Endogenous L-aspartate is released from rat brain synaptosomes
on electrical field stimulation (BRADFORD, 1970).
Postsynaptic Action of L-Aspartate. Feline spinal motoneurones are reversibly
depolarized by L-aspartate (CURTIS, PHILLIS, and WATKINS, 1960) in a manner
similar to that by L-glutamate (Section 3.6). Such a depolarizing action accounts
for the excitant action of L-aspartate on other central neurones.
L-Aspartate Antagonists. All of the L-glutamate antagonists (Section 3.6;
see Fig. 4), excepting LSD which was not tested against L-aspartate, have also
been found to antagonise the excitant action of L-aspartate. Glutamate diethylester
has been reported to be less effective as an aspartate than as a glutamate
antagonist (HALDEMAN and MCLENNAN, 1972). This observation, together with