The baseline efflux of gamma-amino[2,3-3H]butyric acid ([3H]GABA) and [3H]dopamine ([3H]DA) from caudate synaptosomes was greatly enhanced by the sodium-ionophore monensin; this stimulatory effect of monensin on transmitter release was markedly inhibited by trifluoperazine (TFP), a potent calmodulin antagonist. TFP also decreased the depolarization-induced, calcium-dependent release of [3H]GABA and this effect was unrelated to the calcium-flux across the plasma membrane since TFP also inhibited the release of GABA elicited by the calcium-ionophore A23187. Our data indicate that transmitter release induced by both increased intraterminal sodium levels and by the calcium entry into the nerve endings during depolarization might be mediated by calmodulin-dependent processes.