The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms

The kinetic behaviour of [3H]DOPA in living rat brain was investigated by compartmental modelling of measured activities from combined metabolite pools in a time-series (180 min) of static autoradiograms from right cerebral hemispheres. Two models of [3H]DOPA uptake and metabolism that incorporated the removal of the decarboxylation product, [3H]dopamine, from brain were significantly more accurate than a model in which [3H]dopamine accumulated irreversibly in situ. Present estimates of [3H]DOPA kinetic constants were compared to previously published results based on the analysis of measured activities from individual metabolite pools separated by chromatographic fractionation of [3H]DOPA metabolites in the left cerebral hemispheres of the same rats. Autoradiographic estimates of DOPA decarboxylase activity with respect to [3H]DOPA in brain (k3DOPA) were under-estimated several-fold relative to chromatographic estimates; this discrepancy is explained by post-mortem enzyme activity and omission of biological compartments from the models. However, autoradiographic estimates of the unidirectional blood-brain clearance of [3H]DOPA (K1DOPA) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7DA') agreed with chromatographic estimates. This concordance represents the first empirical validation of compartmental modelling of autoradiographic data as a method for quantitatively investigating the kinetic behaviour of radiolabelled L-DOPA in living mammalian brain.

[1]  M. Horne,et al.  The cerebral metabolism of L-dihydroxyphenylalanine. An autoradiographic and biochemical study. , 1984, Pharmacology.

[2]  A. Gjedde,et al.  Regulation of DOPA Decarboxylase Activity in Brain of Living Rat , 1995, Journal of neurochemistry.

[3]  C. Patlak,et al.  Combined FDOPA and 3OMFD PET studies in Parkinson's disease. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[4]  P. Soares-da-Silva,et al.  A kinetic study of the rate of formation of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the brain of the rat: Implications for the origin of dopac , 1990, Neuropharmacology.

[5]  C Nahmias,et al.  A Rostrocaudal Gradient for Aromatic Acid Decarboxylase in the Human Striatum , 1987, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[6]  C S Patlak,et al.  Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data , 1983, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  A. Gjedde,et al.  [3H]DOPA Formed from [3H]Tyrosine in Living Rat Brain Is Not Committed to Dopamine Synthesis , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[8]  A. Gjedde,et al.  On the accuracy of an [18F]FDOPA compartmental model: evidence for vesicular storage of [18F]fluorodopamine in vivo , 1997, Journal of Neuroscience Methods.

[9]  A. Gjedde,et al.  A Kinetic Analysis of 6‐[18F]Fluoro‐l‐Dihydroxyphenylalanine Metabolism in the Rat , 1994, Journal of neurochemistry.

[10]  Scott T. Grafton,et al.  Kinetics and Modeling of l-6-[18F]Fluoro-DOPA in Human Positron Emission Tomographic Studies , 1991, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[11]  A. Gjedde,et al.  Blood—Brain Transfer and Metabolism of 6-[18F]Fluoro-L-DOPA in Rat , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[12]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[13]  A. Gjedde,et al.  Compartmental analysis of dopa decarboxylation in living brain from dynamic positron emission tomograms , 1998, Synapse.

[14]  J. Korf,et al.  TURNOVER OF FREE AND CONJUGATED (SULPHONYLOXY) DIHYDROXYPHENYLACETIC ACID AND HOMOVANILLIC ACID IN RAT STRIATUM , 1979, Journal of neurochemistry.

[15]  L Wahl,et al.  Quantification of dopamine metabolism in man: a mathematically justifiable approach. , 1996, Physics in medicine and biology.

[16]  G. Sperk,et al.  Topographical distribution of amines and major amine metabolites in the rat striatum , 1986, Brain Research.

[17]  L. Descarries,et al.  Dopaminergic nerve endings visualised by high-resolution autoradiography in adult rat neostriatum , 1980, Nature.

[18]  H. Fibiger,et al.  Formation and Clearance of Interstitial Metabolites of Dopamine and Serotonin in the Rat Striatum: An In Vivo Microdialysis Study , 1992, Journal of neurochemistry.

[19]  A. Gjedde,et al.  In Vivo Regulation of DOPA Decarboxylase by Dopamine Receptors in Rat Brain , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[20]  C. Nahmias,et al.  Dopamine visualized in the basal ganglia of living man , 1983, Nature.

[21]  R. Katzman.,et al.  3-0-Methyldopa uptake and inhibition of L-dopa at the blood-brain barrier , 1975 .

[22]  Alan C. Evans,et al.  Human Striatal l-DOPA Decarboxylase Activity Estimated in vivo Using 6-[18F]fluoro-DOPA and Positron Emission Tomography: Error Analysis and Application to Normal Subjects , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  B. Westerink,et al.  Estimation of the Turnover of 3‐Methoxytyramine in the Rat Striatum by HPLC with Electrochemical Detection: Implications for the Sequence in the Cerebral Metabolism of Dopamine , 1982, Journal of neurochemistry.

[24]  T. Ishikawa,et al.  Fluorodopa Positron Emission Tomography with an Inhibitor of Catechol-O-Methyltransferase: Effect of the Plasma 3-O-Methyldopa Fraction on Data Analysis , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[25]  A. Greenshaw,et al.  β‐Adrenergic Effects on Plasma and Brain Large Neutral Amino Acids Are Unaltered by Chronic Administration of Antidepressants , 1991, Journal of neurochemistry.

[26]  P. Moleman,et al.  Haloperidol inhibits the disappearance of acidic dopamine metabolites from rat striatum , 1978, The Journal of pharmacy and pharmacology.

[27]  A. Gjedde,et al.  On the Rate of Decarboxylation of Dopa to Dopamine in Living Mammalian Brain a , 1997, Annals of the New York Academy of Sciences.

[28]  C. Nahmias,et al.  Modeling of fluorine-18-6-fluoro-L-Dopa in humans. , 1996, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[29]  M. Reivich,et al.  THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1 , 1977, Journal of neurochemistry.

[30]  A. Gjedde,et al.  Metabolism and blood-brain clearance of L-3,4-dihydroxy-[3H]phenylalanine ([3H]DOPA) and 6-[18F]fluoro-L-DOPA in the rat. , 1995, Biochemical pharmacology.

[31]  Michael E. Phelps,et al.  Quantitation in Positron Emission Computed Tomography , 1980 .

[32]  Albert Gjedde,et al.  Calculation of cerebral glucose phosphorylation from brain uptake of glucose analogs in vivo: A re-examination , 1982, Brain Research Reviews.

[33]  A. Gjedde,et al.  Brain uptake of α‐[14C]methyl‐para‐tyrosine in the rat , 1994 .

[34]  A. Luxen,et al.  Comparative in vivo metabolism of 6-[18F]fluoro-L-dopa and [3H]L-dopa in rats. , 1990, Biochemical pharmacology.

[35]  Alan C. Evans,et al.  Dopa decarboxylase activity of the living human brain. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[36]  Q. Smith.  The blood-brain barrier and the regulation of amino acid uptake and availability to brain. , 1991, Advances in experimental medicine and biology.

[37]  A. Gjedde,et al.  Quantification of Neuroreceptors in the Living Human Brain. I. Irreversible Binding of Ligands , 1986, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[38]  Paul Cumming,et al.  The effect of unilateral neurotoxic lesions to serotonin fibres in the medial forebrain bundle on the metabolism of [3H]DOPA in the telencephalon of the living rat , 1997, Brain Research.

[39]  L. Potter,et al.  A pre-positron emission tomography study of l-3,4-dihydroxy-[3H]phenylalanine distribution in the rat , 1985, Neuroscience Letters.

[40]  C Nahmias,et al.  Cerebral Metabolism of 6–[18F]Fluoro‐l‐3,4‐Dihydroxyphenylalanine in the Primate , 1987, Journal of neurochemistry.

[41]  J. Saura,et al.  Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19- 6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[42]  Albert Gjedde,et al.  High‐ and Low‐Affinity Transport of D‐Glucose from Blood to Brain , 1981, Journal of neurochemistry.

[43]  G. Wooten,et al.  Dopamine turnover estimated by simultaneous LCEC assay of dopamine and dopamine metabolites. , 1982, Journal of pharmacological methods.

[44]  S. Cherry,et al.  Radiofluorinated L-m-Tyrosines: New In-Vivo Probes for Central Dopamine Biochemistry , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[45]  T. Nagatsu,et al.  Aromatic L-amino acid decarboxylase activity in central and peripheral tissues and serum of rats with L-DOPA and L-5-hydroxytryptophan as substrates. , 1981, Biochemical pharmacology.

[46]  J C Mazziotta,et al.  Quantitation in Positron Emission Computed Tomography: 5. Physical–Anatomical Effects , 1981, Journal of computer assisted tomography.

[47]  W H Oldendorf,et al.  Amino acid assignment to one of three blood-brain barrier amino acid carriers. , 1976, The American journal of physiology.