The uptake and efflux of 54Mn and 45Ca, and the release of dopamine (DA) were measured in pinched-off presynaptic nerve endings (synaptosomes) isolated from rat brain. The uptake of Mn and Ca was increased when forebrain or striatal synaptosomes were incubated in a depolarizing, K-rich solution. The time courses of K-stimulated Mn and Ca entry were similar: there was initially a high rate of ion accumulation, lasting 1-3 s, that gradually levelled off. The initial uptake of Mn, like that of Ca, was greatly diminished by a 10 s pre-incubation in K-rich solution prior to the addition of radiotracer. Several Ca channel blockers, including Ni (0.03 mM), Sr (2.0 mM), Co (0.04 mM), Ba (1.5 mM) and La (0.2 mM), suppressed the K-stimulated uptake of Mn and of Ca to a similar extent. The K-stimulated uptake of Mn increased as a function of the external Mn concentration, and saturated at high external concentrations of Mn. These high concentrations of Mn also blocked the K-stimulated uptake of Ca. There was a decreased efflux of Ca, but not of Mn, from the synaptosomes when the external Na concentration was reduced. The Na-dependent efflux of Ca was diminished by external Mn, but was unaffected when the synaptosomes were loaded with Mn. The rate of [3H]DA release from striatal synaptosomes was less than 0.001 s-1 in non-depolarizing, low-K solutions, in the absence or presence of Mn and Ca (1 mM). The rate of release was also unchanged in depolarizing, K-rich solutions in the absence of these divalent cations. The addition of 1 mM-Mn to a K-rich solution increased the rate of DA release by about 40%, and the time course of release was linear for at least 30 s. The addition of 1 mM-Ca increased the rate of release nearly 100-fold during the first second, and thereafter the rate of release rapidly declined. Ni (1 mM) and, to a lesser extent, Mg (10 mM) reduced the rate of K-stimulated DA release that is dependent on either Mn or Ca. The pattern of inhibition of DA release resembled the pattern of inhibition of K-stimulated uptake of Mn and Ca. The addition of Mn to K-rich solutions stimulated the release of the neurotransmitters 5-hydroxytryptamine and gamma-aminobutyric acid, but not acetylcholine, from striatal synaptosomes.(ABSTRACT TRUNCATED AT 400 WORDS)