The relationship between development of dopamine (DA) innervation of the striatum and maturation of striatal neuropil has resulted in two hypotheses; (1) DA is important for the final determination of the patch/matrix compartments of the striatum; and (2) DA is necessary for appropriate maturation of neuronal processes of cells (e.g., receptor expression at synapses). DA loss in development does not lead to altered organization of the striosomal and matrix compartments. The development of the D1 and D2 subtypes of the DA receptor is related to development of functionally and neuroanatomically defined striatal compartments: (10 at birth an increase in D1 receptors in the patch compartment related to the maturation of the patch-directed DA afferents; (2) after postnatal day 3 (P3) an increase in D2 receptors in the matrix related to maturation of cholinergic terminals; and (3) a later phase (after P7) in which an increase in D1 receptors in the matrix is correlated with the maturation of the DA afferents in the compartment. Removal of the DA system innervating the patch compartment at P1 preserves the matrix innervations and causes: (1) a loss of DA and of D1 receptors from the patch compartment, (2) no change in D2 receptor density or D1 receptor density in the matrix compartment, and (3) a permanent alteration in the expression of TH MRNA in midbrain neurons giving rise to the later- developing (predominantly matrix-directed) DA system. This is significantly different from what occurs when 6-OHDA lesions to the nigrostriatal DA system are made in the adult, which show neurochemical and behavioral evidence of D2 receptor supersensitivity. Therefore, the expression of DA D1 receptors is critically affected by biochemical maturation of DA afferents at the time when the initiation of receptor proliferation occurs. The data also suggest that the expression of D2 receptors comes under control by DA afferents at a much later postnatal time point. However, it is unclear to what extent the late-developing DA system contributes to the effects of the neonatal DA lesions. The different regulation of DA receptors with these early neonatal lesions may be critically dependent on the plasticity of the late-developing system. Our hypothesis is that DA lesions at different points of development will result in anatomically distinct and receptor specific changes in DA receptor expression. We will also determine to what extent the presynaptic DA systems are affected by neonatal DA lesions, and if permanent alterations in the properties of these systems occur as a consequence of early postnatal damage to the DA system. The principles governing the neonatal plasticity of DA systems can be defined using receptor autoradiographic techniques that directly assess receptor expression and THE MRNA expression by in situ hybridization histochemistry in midbrain neurons. Thus, we propose to examine how 6- OHDA lesions to the patch or matrix directed DA systems at different postnatal times alter DA receptor expression and TH MRNA expression in midbrain DA neurons. Second, determine the latency to and duration of those effects. Third, determine if it is the loss of DA, per se, that is the critical factor in altered receptor expression. These data will be compared to that already available on plasticity of the adult DA system following 6-OHDA lesions.
