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Dopamine neurons from the rostra1 mesencephalic tegmentum of embryonic mouse brain were dissociated and allowed to co-aggregate in vitro with dissociated cells from the embryonic corpus striatum. The differentiation of dopamine neurons in this system was characterized by examining the developmental course of a number of indices of dopaminergic function. Fluorescent cell bodies and patches of punctate pericellular fluorescence due to endogenous dopamine were visualized in the co-aggregates after 14 and 21 days in culture. The punctate pericellular fluorescent pattern resembled that seen in the intact neostriatum. Punctate pericellular fluorescence could be detected in 3and 7-day co-aggregates only if they were exposed to 1 pM dopamine. The density of the pericellular fluorescence increased with time in culture. Endogenous dopamine levels also increased with time in culture, reaching maximal levels of 22 ng/mg of protein at 21 days. The accumulation and retention of exogenous dopamine followed a developmental course similar to that observed for endogenous dopamine content. At 21 days in culture, the co-aggregates accumulated 11 to 13 times as much dopamine as was accumulated by 3-day cultures. The sensitivity to reserpine and 6hydroxydopamine also was examined. Co-aggregates cultured for 7, 14, or 21 days and pretreated with reserpine (lop7 M) for 24 hr were able to accumulate 54%, 5%, and 6% as much dopamine as untreated cultures, respectively. 6-Hydroxydopamine ( lop4 M) pretreatment produced a similar agedependent decrease in the amount of dopamine accumulated. Such co-aggregates cultured for 7,14, and 21 days accumulated 41%, lo%, and 7% as much dopamine as control cultures, respectively. No significant effect of either reserpine or 6-hydroxydopamine pretreatment was observed in 3-day cultures. Dopamine neuron-containing co-aggregates show an age-dependent development of mechanisms for the synthesis, accumulation, and storage of dopamine and are able to elaborate and maintain axons and terminals in culture. Thus, the dopaminergic neurons in these co-aggregates display characteristics of anatomical, biochemical, and pharmacological development similar to those seen in intact brain. Dopaminergic neurons are important determinants of motor, ingestive, emotional, and neuroendocrine functions in animals, including man (Seiden and Dykstra, 1977). Studies on the anatomical and biochemical development of central dopaminergic systems represent an important approach to the understanding of the func1 This research was supported by National Institute of Mental Health Grant MH 28942. These data have been presented in preliminary form at the Society for Neuroscience Annual Meeting, October 1981 (Kotake, C., P. C. Hoffmann, and A. Heller (1981) Sot. Neurosci. Abstr. 7: 847). We thank Eligia Dimapilis and Francis Karapas for technical assistance and Dr. T. G. Heffner for critical comments. * To whom correspondence should be addressed at Department of Pharmacological and Physiological Sciences, The University of Chicago, 947 East 58th Street, Chicago, IL 60637. tional role of dopaminergic neurons in these processes. The ontogeny of central dopaminergic neurons in vivo has been studied in some detail (Coyle, 1974; Coyle and Campochiaro, 1976; Golden, 1973; Lauder and Bloom, 1974; Olson and Seiger, 1972; Percher and Heller, 1972; Seiger and Olson, 1973). However, the complexity of neuronal organization in the intact developing fetal brain as well as difficulties in experimentally manipulating these systems during this time period represent formidable barriers to characterization of the mechanisms which direct this development. Dopaminergic neurons arising in the substantia nigra and ventral tegmental area of the rostral mesencephalic tegmentum (RMT) innervate a number of structures in the mammalian forebrain, including the corpus striatum (CS) (Moore and Bloom, 1978; Ungerstedt, 1971). Re-

the journal of neuroscience/the journal of neuroscience

The biochemical and morphological development of differentiating dopamine neurons co-aggregated with their target cells of the corpus striatum in vitro