Various components of the dopamine system displayed distinct and robust changes in both transcript and protein levels during postnatal development. Thus, the prefrontal cortical DA system shows quite dynamic developmental profiles in relation to DA synthesis, receptor signalling, and DA breakdown which all change as humans grow and mature. Many DA receptor mRNAs showed dynamic changes across development. The most commonly observed developmental pattern was to have the highest expression in the youngest age groups, within the first five years of life followed by a decline in expression with age. The expression of DRD2S, DRD2L, and DRD5 mRNAs all displayed this pattern of downregulation with maturation as did TH and MAOA mRNA. MAOA was the only molecule that showed a pronounced decoupling between mRNA and protein expression with the protein showing an increase with age. MOAB and DRD1 (mRNA and protein) showed a gradual increase in expression with age. Interestingly, DRD1 was unique among the dopamine receptors in terms of its developmental profile and our results suggest that there is an increased role for DRD1 as the human cortex matures.
Previous reports suggest that by early adulthood DRD1 is the most prevalent receptor in the PFC followed by DRD2, DRD4, and DRD5 expression [18, 35]. The results reported here show that while all other receptors are decreasing with age, DRD1 mRNA and protein levels are increasing in postnatal life. The increase in DRD1 mRNA expression with age is consistent with our earlier report in a different cohort that showed an increase in DRD1 mRNA expression in multiple cortical layers in the DLPFC during development  with similar peaks of expression during adolescence and young adulthood. As more age groups are represented in this study our results here suggest that a substantial increase in DRD1 mRNA is evident even earlier at around the time of school age years where mRNA levels were very similar to that of adolescent and young adult age groups.
The DRD1 protein peak in expression appears to occur a few years later in life than that of mRNA expression. DRD1 is critical to PFC cognitive functioning and in particular working memory  and these cognitive processes may not fully mature until the third decade of life [38, 39] Thus, the change in DRD1 from periadolescence into young adulthood happens during a time in development when the cortex and our cognitive behaviour are also maturing suggesting that DA-DRD1 may have an integrative role in higher cortical function.
While DRD1 mRNA and protein expression is low early in cortical development, DRD5 expression is at its highest expression. This pattern of DRD5 expression which is opposite to the DRD1 pattern is interesting, given that both receptors are almost indistinguishable pharmacologically . While all of the DA receptors have been shown to play some role in cognition [41, 42], DRD5 is consistently co-localised with DRD1 on pyramidal neurons in the PFC . DRD5 has a ten-fold higher affinity for DA as compared to DRD1  and our finding of increased early expression of DRD5 suggests that this receptor may play a more salient role in early postnatal cortical development than DRD1. Thus, it may be that each receptor provides a differential contribution to DA's influence over pyramidal neurons, dependent upon whether it is in early life or at maturation .
To date, there are no published reports of the DRD2 short and long isoforms in developing primate or human PFC and results in the developing rodent cerebral cortex have been inconsistent. A recent postnatal study in rodent cortex showed DRD2S and DRD2L mRNA expression peaking in early development which is similar to our results . In contrast, Mack et al., (1991) reported that in whole rat brain extracted mRNA, both isoforms increase expression throughout pre- and postnatal development with the highest levels occurring in adulthood . A third study examined the isoforms in whole brain and found DRD2S peaking at 14 days (approximately infant age in humans) and DRD2L at 28 days (approximately school age years) with mRNA levels declining thereafter . We find that in human PFC, DRD2 transcripts exhibit high expression at birth that declines with age. Our studies show that the developmental decrease in DRD2S (before school age) may occur prior to DRD2L (after school age) suggesting that during the school age period in normal children the balance of DRD2 isoform signalling may favour the long isoform of the receptor. Our earlier study examining DRD2 mRNA in PFC showed that the mRNA was greatest during the first few months of postnatal life in all cortical layers. Increased DRD2 mRNA early in development that is localised to both excitatory [48, 49] and inhibitory [50, 51] neurons, may enable DA to modulate neuronal cell types, especially immature GABA neurons because interneurons, which show protracted maturation,  are still differentiating in human DLFC postnatally . Also there is still considerable growth of cell soma, dendrites, and synapses occurring within the first five years of life  when DRD2 and DRD5 mRNA levels are high and DRD1 levels are lowest. Since DRD2 is negatively coupled to adenylate cyclase, high DRD2 levels may be important for attenuating pyramidal neuron activity when DRD5 is high early in life.
Rodent studies have shown varied results in the developmental pattern of DRD4 mRNA expression [18, 47, 55] as have human studies [56, 57]. The results presented here suggest that DRD4 mRNA expression may be variable throughout postnatal life. Our previous postnatal study of laminar patterns of DRD4 expression did not include the toddler or school age groups but did report that the highest levels of DRD4 mRNA expression occurred in the infant group, particularly in layer V and VI . The lack of robust change in DRD4 we find here suggests that age may not be a strong regulator of DRD4 or that maintaining fairly steady DRD4 is important throughout postnatal life.
As anticipated, TH protein is in greater abundance during the first decade of life and recedes with age . It may be that TH and hence DA are necessary in greater abundance during prenatal and early postnatal brain development in order to stimulate the establishment of other neurons and connections. Indeed, TH fibres appear early in embryonic cortex in the telencephalic wall as early as gestational week 8 in humans . The crucial role of TH in overall development is reinforced by the fact that TH knockout mice do not survive beyond E15.5 . As the PFC develops postnatally, the amount of TH and DA synthesis required may be much less. Our results of high levels of TH early in life in the human DLPFC, now found in two distinct cohorts , suggests that there is a large synthetic demand for dopamine early in life when cortical pyramidal neurons (dendritic and appositions) are still maturing  and inhibitory interneurons are still migrating and differentiating . It is also possible that while TH and thus DA synthesis decline, DA innervation becomes more targeted and circuitry refined so that less DA is required to be effective .
Another way to change the parameters of DA action is to change the time course of action. The genes responsible for the inactivation via degradation of DA were found to vary widely in their developmental profiles, with very significant and distinct patterns of expression and in some cases completely opposite profiles from transcription to protein. MAOA mRNA and COMT mRNA and protein exhibited the highest levels of expression in the earliest age groups, suggesting that DA synthesis may be highest early in life and that increased metabolism of DA (via MAOA) may be required to maintain a biochemical balance. But MAOA protein, MAOB mRNA and protein levels increased with age suggesting that later in life there may be increased breakdown of DA through MAOs and that DA's action may be temporarily restricted.
It is not clear why MAOA mRNA expression declined across development whereas MAOA protein increased throughout development to reach peak levels in young adulthood. Our findings do not appear spurious given that the MAOA mRNA data was confirmed in both the microarray and qPCR studies and the Western results show the immunoreactive band of the expected size and to be robustly expressed. Thus the MAOA mRNA may not be efficiently translated into protein or the MAOA protein may be very unstable early in life. It is also possible that there is a presynaptic increase in MAOA protein due to mRNA that is synthesized in the brain stem and the protein is transported to axon terminals such that mRNA and protein levels would appear uncoupled. Previous binding studies of MAOA in rodent suggest a profile similar to our protein results where MAOA expression increases from P0, plateau around P21 and gradually declines through adulthood [60–62]. In addition, mRNA studies in the rodent are consistent with our mRNA results where MAOA expression declines . However, the low level of MAOA protein in early postnatal life is in contrast to published data on radiolabeled MAOA activity in postmortem human frontal cortex that showed the highest MAOA activity in humans less than one year of age . Further study is needed to resolve if species differences exist or if discrepancies in the developmental profiles of MAOA mRNA, protein expression, and activity levels exist.
Unlike MAOA, MAOB mRNA and protein both increase throughout postnatal life. Having low levels of MAOA protein and MAOB protein expression early in life while DA synthesis is presumably highest and DA breakdown slower due to lower levels of MAOA protein and MAOB protein with perhaps only COMT at higher levels, suggests that the overall actions of dopamine may be prolonged in the infant PFC where presumably more DA is available to be released and where there may be a delay in degradation through MAOA and MAOB. This is particularly true for MAOB which has been shown to have a higher affinity for DA than MAOA  and both MOAs have affinities for other catecholamines as well as serotonin and this may have a more broad influence over monoamine developmental availabilities. Hence, MAOB may play an increasingly significant role in cortical DA metabolism at maturation and in adult life.
COMT mRNA is more prominent in the PFC than in subcortical brain regions . Although the noradrenaline transporter [66, 67], vesicular monoamine transporter 2 (VMAT2) and MAO [64, 68] contribute to DA elimination, COMT is responsible for approximately ~ 60% of all DA degradation in the PFC  and our results suggest that this may be higher earlier in postnatal life. The role of COMT in maintaining DA neurotransmission is clearly an important one. Indeed, the TH data would indicate that DA synthesis and presumably DA itself, is extremely abundant early in life with slightly higher levels of COMT protein. COMT mRNA and protein displayed a decrease in expression. The higher gene expression of COMT early in postnatal development is consistent with a previous report in rat where COMT mRNA was highly visible in cortex, hippocampus, and striatum at day P1 and with higher mRNA levels at P1 in hypothalamic nuclei that diminished with age . However, it is not likely that COMT mRNA and protein levels alone predict COMT activity. In a previous study in human DLPFC we found increasing COMT enzymatic activity with age was associated with the COMT Val158Met polymorphism , although genotype effects on mRNA levels [71, 72] and protein [22, 73] levels are not consistent. Further studies are needed to understand the developmental relationship between COMT genotype, COMT synthesis, COMT activity, and DA levels.