Available information on the dopamine (DA) metabolism of the immature brain is rare. In order to establish a useful animal model we have performed PET experiments in anesthetized neonatal pigs using 6-[18F]-fluoro-L-DOPA (FDOPA) as tracer. In this study, we have simultaneously determined the cerebral blood flow and the rate constant of FDOPA conversion by the aromatic amino acid decarboxylase, the ultimate enzyme in the synthesis of dopamine. The estimated values of FDOPA decarboxylation in the basal ganglia were similar to values calculated in adult animals and humans. However, in contrast to those studies a significant decarboxylation was also found in the frontal cortex and the cerebellum. HPLC analysis of brain samples also revealed extensive and rapid metabolism of FDOPA in the five investigated brain regions. At 8 min after tracer injection about 80% of FDOPA was already converted to FDA and its metabolites. Surprisingly, a rather high fraction (16-21%) of [18F]-fluoro-3-methoxytyramine was found which may indicate a low storage capacity of vesicular DA at this perinatal stage. It is suggested that the findings are related to the ontogenetic development of the dopaminergic system. The knowledge of the regulation of the DA metabolism in the immature brain may have implications for the understanding of neurodevelopmental effects of perinatal oxygen deprivation.
There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. However, the relevant enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore, fluorine-18-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) was used together with positron emission tomography to estimate the activity of the aromatic amino acid decarboxylase in the brain of 10 newborn IUGR piglets (2 to 5 d old; body weight, 908 Ϯ 109 g) and in 10 normal-weight (3 to 5 d old; body weight, 2142 Ϯ 373 g) newborn piglets. The regional transport of FDOPA to the brain and the clearance rate of labeled metabolites from brain tissue were broadly similar in the two groups. However, the regional rate constant for back flux from the brain was markedly increased in IUGR piglets for striatum (72%) and frontal cortex (83%) (p Ͻ 0.05). Furthermore, the rate constant for conversion of FDOPA to fluorodopamine was markedly increased (between 48% in cerebellum and 91% in mesencephalon, p Ͻ 0.05) in all brain regions of IUGR piglets studied. Thus, it is suggested that IUGR induces an up-regulation of aromatic amino acid decarboxylase activity that is not related to alterations in brain oxidative metabolism. An inadequate nutritional supply due to uteroplacental insufficiency or restricted maternal protein intake late in gestation is largely responsible for asymmetrical IUGR (1). Reduced fetal growth can be viewed as a compensation for the reduced supply as long as fetal demand is not critically restricted, leading to decompensation with asphyxia and even death (2). The compromised nutritional state has adverse effects on fetal physiology and metabolism including changes of hormonal homeostasis (3), which are thought to be associated with postnatal growth failure and a greater propensity to develop cardiovascular metabolic disease or behavioral abnormalities later in life (4). Therefore, the period of fetal adaptation, characterized by reduced growth due to restricted glucose and amino acid availability but largely compensated placental respiratory function (5), reflects a functional state that may lead to both acceleration or delay in organ maturation (6, 7).The importance of the intrauterine environment for fetal brain development has been stressed by studies showing persistent behavioral abnormalities in prenatally stressed animals (8). Rats exposed to noise and light stress during the last trimester of pregnancy produce offspring with altered locomo-
ABSTRACT474
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.