Estimation of D2-like Receptor Occupancy by Dopamine in the Putamen of Hemiparkinsonian Monkeys

Abstract

To advance understanding of the neurochemical changes in Parkinson's disease (PD), we compared D2-like dopamine receptor occupancy by dopamine in the control and lesioned putamen of four pig-tailed macaques treated unilaterally with MPTP. PET and in vitro binding techniques were used to measure binding potential (BP*) and density of D2-like dopamine receptors (B max ), respectively. As would be expected in PD, relatively higher values of BP* and B max and less amphetamine-induced decrease in [11 C]raclopride binding were observed in the lesioned compared with the contralateral putamen in each animal. The percent differences between lesioned and contralateral sides were similar whether the measurements were of [ 11 C]raclopride BP* or B max values, measured in vivo and in vitro, respectively. As [ 11 C]raclopride BP* is a measure of the density of D2-like dopamine receptors available for radioligand binding (i.e., not occupied by dopamine), these findings suggest that the fractional occupancy of receptors by endogenous dopamine in the lesioned putamen is nearly equal to that in the contralateral putamen. Therefore, the absolute number of receptors occupied by dopamine, which is a product of receptor density and fractional occupancy by dopamine, is greater in the lesioned than in the contralateral putamen. One possible explanation for the lack of differences in fractional occupancy of D2 receptors by dopamine (despite a loss in available dopamine) is a lesion-induced increase in a portion of low-affinity D2 receptors to a state of high affinity for dopamine.

Extrastriatal D2-like receptors modulate basal ganglia pathways in normal and parkinsonian monkeys

“…Earlier studies in monkeys and other species also suggested that D2LR binding in the pallidum and SNr does not change significantly with MPTP treatment Gnanalingham et al 1993;Hurley et al 1996), contrasting with the evidence that striatal expression of mRNA levels for D2LRs, presumably in medium spiny neurons, is increased in dopamine-depleted monkeys (Chefer et al 2008;Herrero et al 1996;Morissette et al 1996). Given that these neurons project predominately to GPe, one could expect an increased expression of D2 receptor immunoreactivity along striatopallidal axons and terminals.…”

Abnormalities of Dopamine D3Receptor Signaling in the Diseased Brain

“… 53 , 54 For instance, positron emission tomography using [ 11 C]raclopride has shown an increased density of D 2 -class receptors in the putamen nucleus in PD. 55 Also, biochemical, electrophysiological, and behavioral data have shown that DA depletion increases the sensitivity (supersensitivity) of D 2 -class receptors in animals models of PD (e.g., DA depletion induced by reserpine, 56 α-methyl- p -tyrosine, 57 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP], 58 and 6-hydroxydopamine [6-OHDA]). 49 , 59 , 60 In the 6-OHDA model, electrophysiological recordings in striatal MSNs have shown that D 3 R signaling contributes to the D 2 -class supersensitivity, 43 , 49 thus suggesting that DA depletion may increase D 3 R expression and activity.…”

Decreased binding of the D3 dopamine receptor-preferring ligand [11C]-(+)-PHNO in drug-naive Parkinson's disease

“…Given the selectivity of [ 11 C]-(+)-PHNO for the D high 2 receptor (i.e. : unlike [ 11 C]raclopride which binds to both the DA receptor in high-and low-affinity states) (Seeman et al, 1993), an alternative explanation is that decreased Chefer et al, 2008) or in vivo (Cumming et al, 2003) is sustained by many in vitro studies, it is unclear whether this state of the receptor can actually be measured in vivo (Sibley et al, 1983;McCormick et al, 2008).…”