Dopa decarboxylase activity of the living human brain.

Abstract

Monoamiergic neurons use dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28) to form dopamine from L-3,4-dihydroxyphenylalanine (L-dopa). We measured regional dopa decarboxylase activity in brains of six healthy volunteers with 6-[18F]fluoro-L-dopa and positron emission tomography. We calculated the enzyme activity, relative to its K., with a kinetic model that yielded the relative rate of conversion of 6['8Flfluoro-L-dopa to [18Fjfluorodopamine. Regional values of relative dopa decarboxylase activity ranged from nil in occipital cortex to 1.9 h-1 in caudate nucleus and putamen, in agreement with values obtained in vitro.The accumulation of metabolites of 6-[18F]fluoro-L-dopa (Fdopa) in brain reflects the activity of dopa decarboxylase (DDC; aromatic-L-amino-acid carboxy-lyase, EC 4.1.1.28), the enzyme responsible for the formation of dopamine from dopa (3,4-dihydroxyphenylalanine) (1-3). Unlike tyrosine hydroxylase, this enzyme is believed not to be regulated in response to the intensity of dopaminergic neurotransmission (4). Therefore, DDC activity may be a more precise indicator of the tissue's capacity to synthesize dopamine than tyrosine hydroxylase, the activity of which is adjusted to compensate for changes of dopaminergic activity.Recently, we used Fdopa to measure the relative activity ofDDC in vivo in rat brain (5). We defined the relative activity as the ratio between the reaction velocity and the enzyme precursor content ofthe tissue-i.e., proportional to the ratio between the enzyme's maximal velocity and the halfsaturation concentration of precursor when the precursor concentration is negligible relative to the half-saturation Michaelis constant Km (see Eqs. 7 and 8). In rat brain, the relative enzyme activity was as low as 1% of the relative activity reported in vitro. The reason for the discrepancy was unknown, but we speculated that it most probably was the loss of labeled fluorodopamine or its metabolites from one or more pools of dopamine in the tissue.In the present study, we obtained the relative activity of DDC in human brain in vivo. In vitro, the monoamine oxidase activities are lower in human brain than in rat brain (see Discussion), and metabolite diffusion distances are longer. For these reasons, we predicted the human relative DDC activity, determined in striatum in vivo with positron emission tomography (PET), to be close to the relative rate of dopamine synthesis determined in vitro. METHODSA model of the transport and metabolism of Fdopa in brain in vivo must include the compartments and transfer coefficients shown in Fig. 1. The model describes the methylation of Fdopa in the circulation (actually in peripheral organs), the loss of methyl-Fdopa from the circulation, the methylation of Fdopa in brain tissue, the exchange of Fdopa and methylFdopa between the circulation and brain tissue, and the decarboxylation of Fdopa in the tissue. The model has too many compartments to be evaluated by PET. We used known relationships between the parameters to reduc...

Effects of the Antipsychotic Risperidone on Dopamine Synthesis in Human Brain Measured by Positron Emission Tomography with l-[β-11C]DOPA: A Stabilizing Effect for Dopaminergic Neurotransmission?

“…Increases and decreases in the activity of aromatic L-amino acid decarboxylase (AADC) by antagonists and agonists of dopamine D 2 receptors were also observed in rat brain tissue, respectively (Zhu et al, 1992(Zhu et al, , 1993. The regional activity of AADC in brain indicating the dopamine synthesis capacity can be estimated using radiolabeled L-DOPA (Gjedde et al, 1991). Significant increases and decreases in dopamine synthesis capacities by antagonists and agonists of dopamine D 2 receptors were observed in animal studies using [ (Cumming et al, 1997;Torstenson et al, 1998;Danielsen et al, 2001).…”

PET Studies of Net Blood—Brain Clearance of FDOPA to Human Brain: Age-Dependent Decline of [18F]Fluorodopamine Storage Capacity

“…The activity of DOPA decarboxylase is assumed to be zero in the cerebellum reference region, but elsewhere FDOPA is decarboxylated at the rate constant k 3 D (min À1 ). The product [ 18 F]fluorodopamine formed in the brain, together with its subsequent metabolites, is assumed to diffuse from the brain as a single compartment at the rate constant k loss (min À1 ) (modified after Gjedde et al, 1991). , was fixed to the mean experimentally determined value of 1.5 , the two amino acids are assumed to have a common blood-brain partition volume (…”

Subchronic Haloperidol Downregulates Dopamine Synthesis Capacity in the Brain of Schizophrenic Patients In Vivo

“…A constrained two-compartment model assuming irreversible trapping in the brain of decarboxylated metabolites was fitted to the timeradioactivity curves (TACs) recorded in brain (Gjedde et al, 1991;Huang et al, 1991). The temporal changes in the plasma concentrations of FDOPA and its principal metabolite O-methyl-FDOPA were used to calculate the apparent first-order rate constant for the formation of O-methyl-FDOPA (k D 0 , min À1 ), corresponding to the whole-body activity of catechol-O-methyltransferase, and the fractional rate constant for the elimination of…”

“…Here, the solution of the twocompartment model is facilitated by constraining the magnitude of V e D to the individual observation obtained in the cortical reference region. This approach allows stable estimates of the term of interest, the local relative activity of DOPA decarboxylase k D 3 Gjedde et al, 1991;Huang et al, 1991). Thus, the parameters to be estimated in the ROIs were the apparent plasma volume occupied by FDOPA V o (ml g À1 ), the local magnitude of K D 1 , and the magnitude of k D 3 .…”