The effects of MPTP on non-dopaminergic neurons were studied in the striatum of ICR mice, by means of enzyme histochemistry for neurons containing acetylcholinesterase (AChE) or NADPH(2)-diaphorase and of immunohistochemistry for neurons containing GABA, serotonin or enkephalin. The most prominent changes were observed in immunohistochemical staining for enkephalin, 3 days after the treatment with MPTP. Enkephalinimmunoreactive nerve fibers and terminals were increased both in number and in intensity, particularly at enkephalin-rich islands seen in the rostral striatum. In addition, enkephalin-positivepass-through fibers and cell bodies were also increased throughout the striatum. The highest density of these cell bodies was found in the caudal striatum. These changes in enkephalin immunoreactivity became less evident day by day, and 60 days later the staining result appeared almost the same as that in control mice. In contrast, serotonin-immunoreactive nerve fibers became sparse, particularly in ventrolateral parts of the striatum, from 7 days after the treatment with MPTP. Such a change was obsesved for as long as 60 days, so that it was suggested that the MPTP treatment caused irreversible degenerative changes in serotonin nerve terminals of the striatum. On the other hand, no significant change was recognized in other striatal nerons containing AChE, NADPH(2)-diaphorase or GABA. The present study indicates that some non-dopaminergic neurons, either intrinsic or extrinsic to the striatum, are affected by the MPTP treatment and therefore an important to the understanding of the etiology of Parkinson's disease.