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Estimation of D2-like dopamine receptor occupancy by dopamine in the MPTP primate model of Parkinson's disease
T144
Poster Presentations / NeuroImage 31 (2006) T44 – T186
Poster Presentation No.: 093
Estimation of D2-like dopamine receptor occupancy by dopamine in the MPTP primate model of Parkinson’s disease Svetlana Chefer,1 A. Kimes,1 E. Domino,2 E. London,3 A. Mukhin 1 1
Neuroimaging Research Branch, NIDA-IRP, NIH, DHHS, Baltimore, MD, USA 2 Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA 3 Department Psychiatry and Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA vivo ) and binding Previous studies with [11C]raclopride and PET demonstrated that both D2-like dopamine (DA) receptor density (Bin max potential (BP*), which reflect the density of these receptors available for radioligand binding (i.e., not occupied by DA), are elevated in patients with Parkinson’s disease (PD) and in a PD animal model compared to control values. Because [11C]raclopride binding in vivo is sensitive to changes in extracellular DA, which is decreased in PD, it is reasonable to expect a greater percent difference from control when vivo in vivo is almost measuring BP* than Bin max . Earlier findings have suggested, however, that the percent difference from control in BP* and B max 11 11 app identical. Consistent with this K D for [ C]raclopride estimated with an assumption that [ C]raclopride interacts in vivo with a single vivo population of binding sites is not different in PD. To address this issue further, we used PET and [11C]raclopride to measure BP* and Bin max in vivo in the bilateral putamen (Put) of monkeys treated unilaterally with MPTP. Given that B max estimation can be complicated by some methodological problems, we subsequently conducted postmortem in vitro binding assays of Put tissue from the same animals using [3H]raclopride. We observed that despite indication of PD in the lesioned Put (upregulation of D2 receptors and reduction in amphetamineinduced DA release) the percent increase in [11C]raclopride BP* values was similar to the percent increase in B max measured in vivo and in vitro vitro (Bin max ). These data suggest that the fractional receptor occupancy by DA in the lesioned Put is not lower than in control Put. Based on vivo vitro our finding that the percent changes in Bin and Bin in the lesioned Put were similar, we used Eq. 1 to calculate the changes in receptor max max occupancy by DA in the lesioned Put (DF occ(L)) using published data [1]. 1 DFoccðLÞ % ¼ 1 ð1 S Þ% FoccðCÞ
where S¼
BPL BPC
BmaxðLÞ BmaxðCÞ
Analyses of the results from all four independent studies, including the present one, were consistent and suggest that the fractional receptor occupancy by DA in PD is not changed. Furthermore, it is rather increased (by 8 T 7%) than decreased. Since D2 receptor density is elevated in PD (by 26 – 45%), the absolute number of receptors occupied by DA in PD is clearly elevated. One potential mechanism explaining the absence of changes in fractional D2 receptor occupancy by DA could be a shift in a portion of low affinity receptors to high affinity state. These changes might mask the effect of reduced DA. New PET radioligands selective for high affinity D2 DA receptors would facilitate testing this hypothesis. Reference: Rinne, et al., 1995; Doudet et al., 2002, 2003. doi:10.1016/j.neuroimage.2006.04.127
Poster Presentations / NeuroImage 31 (2006) T44 – T186
Poster Presentation No.: 093
Estimation of D2-like dopamine receptor occupancy by dopamine in the MPTP primate model of Parkinson’s disease Svetlana Chefer,1 A. Kimes,1 E. Domino,2 E. London,3 A. Mukhin 1 1
Neuroimaging Research Branch, NIDA-IRP, NIH, DHHS, Baltimore, MD, USA 2 Department of Pharmacology, University of Michigan, Ann Arbor, MI, USA 3 Department Psychiatry and Pharmacology, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA vivo ) and binding Previous studies with [11C]raclopride and PET demonstrated that both D2-like dopamine (DA) receptor density (Bin max potential (BP*), which reflect the density of these receptors available for radioligand binding (i.e., not occupied by DA), are elevated in patients with Parkinson’s disease (PD) and in a PD animal model compared to control values. Because [11C]raclopride binding in vivo is sensitive to changes in extracellular DA, which is decreased in PD, it is reasonable to expect a greater percent difference from control when vivo in vivo is almost measuring BP* than Bin max . Earlier findings have suggested, however, that the percent difference from control in BP* and B max 11 11 app identical. Consistent with this K D for [ C]raclopride estimated with an assumption that [ C]raclopride interacts in vivo with a single vivo population of binding sites is not different in PD. To address this issue further, we used PET and [11C]raclopride to measure BP* and Bin max in vivo in the bilateral putamen (Put) of monkeys treated unilaterally with MPTP. Given that B max estimation can be complicated by some methodological problems, we subsequently conducted postmortem in vitro binding assays of Put tissue from the same animals using [3H]raclopride. We observed that despite indication of PD in the lesioned Put (upregulation of D2 receptors and reduction in amphetamineinduced DA release) the percent increase in [11C]raclopride BP* values was similar to the percent increase in B max measured in vivo and in vitro vitro (Bin max ). These data suggest that the fractional receptor occupancy by DA in the lesioned Put is not lower than in control Put. Based on vivo vitro our finding that the percent changes in Bin and Bin in the lesioned Put were similar, we used Eq. 1 to calculate the changes in receptor max max occupancy by DA in the lesioned Put (DF occ(L)) using published data [1]. 1 DFoccðLÞ % ¼ 1 ð1 S Þ% FoccðCÞ
where S¼
BPL BPC
BmaxðLÞ BmaxðCÞ
Analyses of the results from all four independent studies, including the present one, were consistent and suggest that the fractional receptor occupancy by DA in PD is not changed. Furthermore, it is rather increased (by 8 T 7%) than decreased. Since D2 receptor density is elevated in PD (by 26 – 45%), the absolute number of receptors occupied by DA in PD is clearly elevated. One potential mechanism explaining the absence of changes in fractional D2 receptor occupancy by DA could be a shift in a portion of low affinity receptors to high affinity state. These changes might mask the effect of reduced DA. New PET radioligands selective for high affinity D2 DA receptors would facilitate testing this hypothesis. Reference: Rinne, et al., 1995; Doudet et al., 2002, 2003. doi:10.1016/j.neuroimage.2006.04.127