TY - JOUR
T1 - The kinetic behaviour of [3H]DOPA in living rat brain investigated by compartmental modelling of static autoradiograms
AU - Deep, Paul
AU - Kuwabara, Hiroto
AU - Gjedde, Albert
AU - Cumming, Paul
N1 - Funding Information:
This research was supported by grant SP-30 from the Medical Research Council (MRC) of Canada. PD is a recipient of the Jeanne Timmins Costello Student Fellowship of the Montreal Neurological Institute, and a fellowship from the Fonds pour la Formation de Chercheurs et l'Aide à la Recherche (FAR). The authors thank Ms. Christine Laliberté for expert technical assistance. This work is dedicated to Doris (Sept. 27, 1979–Feb. 13, 1997), cherished friend of PD: she is gone, but never forgotten.
PY - 1997/12/30
Y1 - 1997/12/30
N2 - 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 (k3/(DOPA)) 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 (K(l)/(DOPA)) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7/(DA)) 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.
AB - 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 (k3/(DOPA)) 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 (K(l)/(DOPA)) and monoamine oxidase activity with respect to [3H]dopamine in brain (k7/(DA)) 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.
KW - Blood-brain clearance
KW - Chromatographic fractionation
KW - Compartmental model
KW - DOPA decarboxylase activity
KW - Kinetic constants
KW - Rat brain
KW - [H]DOPA autoradiography
KW - [H]Dopamine
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U2 - 10.1016/S0165-0270(97)00147-7
DO - 10.1016/S0165-0270(97)00147-7
M3 - Article
C2 - 9497012
AN - SCOPUS:0031592236
SN - 0165-0270
VL - 78
SP - 157
EP - 168
JO - Journal of Neuroscience Methods
JF - Journal of Neuroscience Methods
IS - 1-2
ER -