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The release of preloaded [14C]neuroactive amino acids (glutamic acid, proline, gamma-aminobutyric acid) from rat brain synaptosomes can occur via a time-dependent, Ca2+-independent process. This Ca2+-independent efflux is increased by compounds that activate Na+ channels (veratridine, scorpion venoms), by the ionophore gramicidin D, and by low concentrations of unsaturated fatty acids (oleic acid and arachidonic acid). Saturated fatty acids have no effect on the efflux process. Neither saturated nor unsaturated fatty acids have an effect on the release of [14C]leucine, an amino acid not known to possess neurotransmitter properties. The increase in the efflux of neuroactive amino acids by oleic and arachidonic acids can also be demonstrated using synaptosomal membrane vesicles. Under conditions in which unsaturated free fatty acids enhance amino acid efflux, no effect on 22Na+ permeability is observed. Since Na+ permeability is not altered by fatty acids, the synaptosomes are not depolarized in their presence and, thus, the Na+ gradient can be assumed to be undisturbed. We conclude that unsaturated fatty acids represent a potentially important class of endogenous modulators of neuroactive amino acid transport in nerve endings and further postulate that their action is the result of an uncoupling of amino acid transport from the synaptosomal Na+ gradient.

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