Ontogeny of dopaminergic function in the rat midbrain tegmentum, corpus striatum and frontal cortex.

Ontogenic development of the dopaminergic system in rat brain was investigated. This was accomplished by monitoring changes in postsynaptic dopamine receptor formation and presynaptic dopamine content in the midbrain tegmentum, frontal cortex and corpus striatum from the 18th day of gestation through adulthood. The dopamine antagonist spiperone was used as the binding ligand to quantitate receptor number while dopamine content was measured chromatographically. [3H]Spiperone binding kinetics in adult animals revealed that the maximum number of receptor sites (Bmax) was 160, 900 and 597 fmol/mg protein in midbrain tegmentum, frontal cortex and corpus striatum, respectively, while the corresponding equilibrium constant (Kd) values were 0.15, 0.52 and 0.15 nM. During the course of development, the affinity for spiperone binding in corpus striatum and frontal cortex did not change significantly, while in midbrain tegmentum the binding affinity in younger animals was significantly lower. Results from competitive inhibition experiments using various serotonergic and dopaminergic antagonists suggested that at all ages dopamine D2-receptors were responsible for spiperone binding in corpus striatum and midbrain tegmentum. In frontal cortex, binding properties consistent with D2-receptors were observed in non-adult animals; by the time adulthood was reached, however, spiperone binding characteristics were altered and appeared to correspond to serotonin sites. The developmental patterns of the dopaminergic markers were different in all 3 tissues. Adult receptor levels were achieved very early in midbrain tegmentum, while increases in receptor number continued in corpus striatum and frontal cortex, at different rates, throughout the postnatal period. A marked increase in dopamine in corpus striatum occurred during the second and third postnatal weeks and the transmitter content remained relatively constant after this time. Transient fluctuations in endogenous dopamine during the postnatal period were observed in midbrain tegmentum and frontal cortex. A general feature of the ontogenic pattern in all tissues appeared to be increases in dopamine receptor preceding increases in dopamine synthesis. A hypothesis on the developmental regulation of dopamine neurons was derived.