We have examined the effects of L-dihydroxyphenylalanine (L-DOPA) on endogenous dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) efflux from superfused striatal slices prepared from adult male rats. Superfusion with L-DOPA (10 microM) caused a modest elevation in the tissue levels of DA and greatly increased the basal efflux and stimulation-evoked overflow of DA. Stimulation of slices under Ca2(+)-free conditions abolished DA overflow occurring in the absence of L-DOPA, but reduced DA overflow in the presence of L-DOPA by only 56%. Ca2(+)-independent DA release was not reduced by nomifensine. Destruction of DA terminals by pretreatment with 6-hydroxydopamine did not alter the capacity of L-DOPA to elevate tissue DA content. However, it attenuated the impact of L-DOPA on DA efflux, although this effect was somewhat smaller than was the apparent loss of DA terminals. These results suggest the following conclusions: (1) L-DOPA increases both the spontaneous and depolarization-induced release of DA; (2) some of the DA formed from L-DOPA can be released in response to depolarization by a process that does not involve either Ca2(+)-dependent exocytosis or reverse transport; and (3) most but not all of the DA efflux occurring in the presence of L-DOPA represents DA released from DA terminals. Furthermore, the observations suggest that the loss of DA terminals due to the progression of Parkinson's disease may be importantly involved in the gradual loss of clinical efficacy of the drug during chronic treatment.