DEVELOPMENT OF STRIATAL DOPAMINERGIC FUNCTION .1. PRENATAL-DEVELOPMENT AND POSTNATAL-DEVELOPMENT OF MESSENGER-RNA AND BINDING-SITES FOR STRIATAL D1 (D1A) AND D2 (D2A) RECEPTORS

Quantitative receptor autoradiography with iodinated ligands, quantita tive in situ hybridization histochemistry and reverse transcriptase-po lymerase chain reaction (RT-PCR) were used to describe the prenatal an d early postnatal ontogeny (embryonic day 14 to postnatal day 7, or E1 4 to P7) of striatal D1 and D2 dopamine receptor binding sites and mRN A levels, respectively, in relation to the development of dopaminergic nigrostriatal innervation. D1 dopamine receptor, measured by [I-125]S CH23982 binding, and dopamine transporter binding sites, measured by [ I-125]RTI-55 binding, were present in low amounts beginning on E14 (2- 3% and 0.3-0.6% of adult values, respectively) and increased slowly du ring the prenatal period. D2 receptor binding sites, measured with [I- 125]spiperone, were also detected on E14 but in higher relative quanti ties (17% of adult values) than D1 receptor and dopamine transporter b inding sites at the same age. Other than abrupt declines in the late p renatal period for D1 and D2 receptor binding sites, all three binding sites increased throughout development and increased maximally betwee n P7 and adulthood. On P5, both D1 and D2 receptors were functionally coupled to their respective G proteins, based on GTP-induced decreases in affinity of dopamine for [I-125]SCH23982 and [I-125]spiperone bind ing. D1 receptor mRNA was present in E14 striatal anlage, increased pr enatally, declined on PO, then increased to a peak on P5, after which it declined to its lowest levels (20% of peak values) in the adult. In contrast, D2 receptor mRNA levels were present also on E14, increased to a peak on P0, declined until P5, and increased thereafter to adult hood. Anatomically, nigrostriatal innervation and D1 and D2 receptor m RNA levels increased from the medial to lateral striatal quadrants. In contrast, D1 and D2 receptor binding site ontogeny exhibited fairly h omogeneous distributions from E18 to P7. D1 and D2 receptor mRNAs appe ar to be expressed early in prenatal development before there is any s ignificant dopaminergic innervation. In contrast, the majority of D1 a nd D2 receptor binding activity, representing expressed receptor prote ins, develops in the postnatal period and correlates well with the inc rease in dopaminergic innervation. Intrinsic genetic programming is mo re likely to be responsible for D1 and D2 receptor gene transcription in striatal neuroblasts and newly born neurons, while factors derived from ingrowing dopaminergic afferents may direct post-transcriptional dopamine receptor development. The dissociation between the ontogeny o f dopamine receptor binding sites and mRNAs suggests that the developm ental regulation of D1 and D2 receptor synthesis is independent of D1 and D2 receptor gene transcription.