In vivo PET studies of the dopamine D1 receptors in rhesus monkeys with long-term MPTP-induced Parkinsonism.

Abstract

The status of the dopamine (DA) D1 receptors after degeneration of the DA-nigrostriatal neurons, either in Parkinson’s disease (PD) or experimental parkinsonism induced by neurotoxins such as 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OH-DA), is unclear. While an abundant literature of postmortem and in vivo data exists, the reports are often contradictory. In humans, monkeys, and rodents with parkinsonism, the striatal DA D1 receptors have been reported increased (Gnanalingham et al., 1993; Iwata et al., 1996; Rioux et al., 2001), unchanged (Alexander et al., 1991; Graham et al., 1990; Laihinen et al., 1994; Rinne et al., 1990; Shinotoh et al., 1993), and decreased (Marshall et al., 1989; Turjanski et al., 1997). Studies of D1 receptor mRNA are as confusing as those of receptor binding, with both decreases (Goulet et al., 1997) and no changes (Hurley et al., 2001) reported and correlate poorly with D1 binding in the same subject. Part of the confusion may rest with differences in the severity of the disease/ lesion, its duration, the tracer used, and/or the different methodological approaches used. In addition, in PD patients the influence of previous antiparkinsonian therapy before measurement or assay has also been shown to affect the results (Raisman et al., 1985). In this study, we measured the binding potential of [C]-SCH23390, a tracer widely used to study DA D1 receptors both in vivo and in vitro, in rhesus monkeys, normal and with MPTP-induced lesions of the DA nigrostriatal pathway. The normal controls were housed with the MPTP-lesioned animals and were exposed to the same living conditions and anesthetic regimens. Thus, the main differences between the animals resided in the degree of MPTP-lesion, which was assessed by in vivo measurements of 6-[F]fluoro-L-dopa (FDOPA) uptake in an earlier study (Doudet et al., 1998). This population was an ideal means to resolve the controversy over DA D1 binding in vivo. MATERIALS AND METHODS