Abstract The calcium ionophore A-23187, at a concentration of 250 μg/ml, had no significant effects on the efflux of ( 3H)-noradrenaline or of ( 14C)-α-aminoisobutyrate, in superfused slices from rat neocortex. Sodium-deficient solutions (sodium partly substituted by choline), however, were found to increase the efflux of ( 14C)-α-aminoisobutyrate and of ( 3H)-γ-aminobutyrate. The enhanced efflux of both these substances appeared with no latency, was maintained for long periods, and did not change appreciably when calcium was omitted. Media low in sodium enhanced noradrenaline efflux in a more complex manner. There was, initially, a small increase in efflux that was similar both in latency and lack of dependence upon calcium to that of the above amino acids. This was followed by a very large efflux peak of noradrenaline, with a change in the fractional rate constant of up to 0.06 min −1. This large efflux peak did not occur when no calcium was added to the superfusing fluid. The efflux of noradrenaline occurred when calcium was replaced by strontium or barium ions, but the latter were less effective. Finally, when media free of added calcium were made sodium-deficient, there was a moderate increase in the efflux of noradrenaline that began after a delay of about 30 min. It is suggested that the effects of sodium-deficient media on the efflux of amino acids and transmitters are due to two different mechanisms. The first mechanism involves interference with sodium-dependent active transport processes that carry substances from the extracellular fluid across the plasma membrane; this could account for the increased efflux of α-aminoisobutyrate and of γ-aminobutyrate and for the first, small, increased efflux of noradrenaline, all of which are independent of external calcium concentration. The second mechanism is mediated by an increase in intracellular calcium, induced by low external sodium, which promotes secretion of noradrenaline present in synaptic vesicles. The large efflux of noradrenaline, that is calcium-dependent, might be the result of this mechanism. In addition, solutions low in both sodium and calcium induce non-specific increases in membrane permeability, that lead to the delayed release of noradrenaline.