Cholinergic Neuronal Modulation Alters Dopamine D₂Receptor Availability In Vivo by Regulating Receptor Affinity Induced by Facilitated Synaptic Dopamine Turnover: Positron Emission Tomography Studies with Microdialysis in the Conscious Monkey Brain

Abstract

To evaluate the cholinergic and dopaminergic neuronal interaction in the striatum, the effects of scopolamine, a muscarinic cholinergic antagonist, on the striatal dopaminergic system were evaluated multi-parametrically in the conscious monkey brain using high-resolution positron emission tomography in combination with microdialysis. L-3,4-Dihydroxyphenylalanine (L-[␤-11 C]DOPA) and 2␤-carbomethoxy-3␤-(4-fluorophenyl)-tropane ([␤-11 C]CFT) were used to measure dopamine synthesis rate and dopamine transporter (DAT) availability, respectively. For assessment of dopamine D 2 receptor binding in vivo, [ 11 C]raclopride was applied because this labeled compound, which has relatively low affinity to dopamine D 2 receptors, was hypothesized to be sensitive to the striatal synaptic dopamine concentration. Systemic administration of scopolamine at doses of 10 and 100 g/kg dose-dependently increased both dopamine synthesis and DAT availability as measured by L-[␤-11 C]DOPA and [␤-11 C]CFT, respectively. Scopolamine decreased the binding of [ 11 C]raclopride in a dose-dependent manner. Scopolamine induced no significant changes in dopamine concentration in the striatal extracellular fluid (ECF) as determined by microdialysis. However, scopolamine dose-dependently facilitated the striatal ECF dopamine induced by the DAT inhibitor GBR12909 at a dose of 0.5 mg/kg. Scatchard plot analysis in vivo of [ 11 C]raclopride revealed that scopolamine reduced the apparent affinity of dopamine D 2 receptors. These results suggested that the inhibition of muscarinic cholinergic neuronal activity modulates dopamine turnover in the striatum by simultaneous enhancement of the dynamics of dopamine synthesis and DAT availability, resulting in no significant changes in apparent "static" ECF dopamine level but showing a decrease in [ 11 C]raclopride binding in vivo attributable to the reduction of affinity of dopamine D 2 receptors.

Modulation of Amphetamine-Induced Dopamine Release by Group II Metabotropic Glutamate Receptor Agonist LY354740 in Non-Human Primates Studied with Positron Emission Tomography

“…Administration of drugs (such as nicotine) that do increase DA cell firing and DA synaptic concentration without blocking the DAT are associated with reduced [ 11 C]raclopride binding in the absence of detectable changes in extracellular DA measured with microdialysis (Kim et al, 1998;Tsukada et al, 1999aTsukada et al, , b, 2000. The reason for this apparent discrepancy is that the DAT are effective at preventing the diffusion of synaptic DA to the extracellular space (Tsukada et al, 2000). Thus, [ 11 C]raclopride imaging provides a more direct measure of D 2 receptor stimulation by DA than microdialysis (see, for further discussion, Laruelle, 2000).…”

Chronic NMDA Antagonism Impairs Working Memory, Decreases Extracellular Dopamine, and Increases D1 Receptor Binding in Prefrontal Cortex of Conscious Monkeys

“…One possible explanation for reduced binding in PFC might be competition between [ 11 C]FLB457 and synaptic DA enhanced by NMDA inhibition based upon a conventional 'occupancy' theory. This is unlikely, however, because Okauchi et al (2001) previously reported that methamphetamine did not affect [ 11 C]FLB457 binding to extrastriatal D 2 R, suggesting the insensitivity of [ 11 C]FLB457 for synaptic DA, probably because of its high affinity to D 2 R. Instead of the conventional 'occupancy' theory, another explanation may be a 'rate' theory defined as the dynamics of DA binding to receptors and the synaptic turnover of DA (Tsukada et al, 1999a(Tsukada et al, , 2000a. Further studies are needed on the modulation of [ 11 C]FLB457 binding to extrastriatal D 2 R. In contrast to D 2 R, no significant changes in [ 11 C]NNC112 binding to PFC D 1 R were detected in the acute study.…”

Evaluation of 6-11C-Methyl-m-Tyrosine as a PET Probe for Presynaptic Dopaminergic Activity: A Comparison PET Study with β-11C-l-DOPA and 18F-FDOPA in Parkinson Disease Monkeys

“…18 F-FDOPA uptake reflects the activity of aromatic L-amino acid decarboxylase (AADC) in the nerve terminals of the nigrostriatal dopaminergic pathway, and the metabolized 18 F-fruoro-dopamine ( 18 F-FDA) is stored in the vesicles through vesicular monoamine transporter. We have applied b-11 C-L-DOPA (5) to monitor dopamine synthesis rate facilitated by pharmacologic manipulations in normal monkeys (6,8,9) as well as impaired (10) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD model monkeys (11). Because these research studies required multiparametric PET assessments of presynaptic dopamine synthesis, DAT, and postsynaptic dopamine receptors in the same subject in a day, the short half-life of 11 C is very useful for the repeated PET measurements.…”