ABSTRACT
In the late 1950s a number of investigations were carried out concerning the effects of amino acids on the excitability of neurones in the cerebral cortex and spinal cord. Dusser de Barrenne introduced the method in 1933 of applying certain substances, such as strychnine, directly to the cortex of animals and observing the changes in behavior of the animal as well as of electrical discharges from other parts of the cortex. Hayashi refined this technique and in a series of papers beginning as far back as 1952 showed that acidic amino acids such as glutamate cause clonic convulsions when applied directly to the cortex of a dog (see Hayashi, 1952, 1956; for a review see Takagaki, 1996). He also showed, in several different mammalian species, that 4-aminobutyrate (gamma-aminobutyric acid, GABA) acted on the brain, and suggested that this might be the inhibitory transmitter (Hayashi & Nagai, 1952). This seemed particularly persuasive as both GABA and the activity of GABAsynthesizing enzyme (L-glutamate carboxy-1-lyase, glutamate decarboxylase, GAD, EC 4.1.1.15) had been known to be present at particularly high levels in the mammalian brain (Awapara et al., 1950; Roberts et al., 1950; Udenfriend, 1950; Roberts & Frankel, 1951). Subsequently both van Harreveld (1959) and Purpura et al. (1959) used the approach of applying substances to the cerebral cortex and observing the resultant changes in field potentials in order to produce a systematic study of the effects of amino acids on excitability. Van Harreveld (1959) discovered that extracts of rabbit pallium cause contractions of crustacean muscles in high dilutions and that the active principle was glutamic acid, suggesting that this may be an excitatory transmitter. This appeared to be especially the case given that Robbins (1959) had shown the excitant effects of glutamic acid on crustacean muscle, and concluded that ‘The possibility that L-glutamic acid is the E transmitter at this neuromuscular junction is compatible with the results’. Robbins (1959) also noted that GABA acted to inhibit muscle contractions in crustacean muscle, as others had noted (Blazemore et al., 1956), and that this effect was blocked by picrotoxin (Van der Kloot et al., 1958). Florey (1957) had already concluded that GABA was the transmitter at inhibitory synapses and Robbins concluded that ‘The most likely mode of action is that GABA combines with the I receptor in the post-junctional membrane’.
