Cholinergic neuronal modulation alters dopamine D-2 receptor availability in vivo by regulating receptor affinity induced by facilitated synaptic dopamine turnover: Positron emission tomography studies with microdialysis in the conscious monkey brain

To evaluate the cholinergic and dopaminergic neuronal interaction in the st riatum, the effects of scopolamine, a muscarinic cholinergic antagonist, on the striatal dopaminergic system were evaluated multi-parametrically in th e conscious monkey brain using high-resolution positron emission tomography in combination with microdialysis. L-3,4-Dihydroxyphenylalanine (L-[beta-C -11]DOPA) and 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane ([beta-C-1 1]CFT) were used to measure dopamine synthesis rate and dopamine transporte r (DAT) availability, respectively. For assessment of dopamine D-2 receptor binding in vivo, [C-11]raclopride was applied because this labeled compoun d, which has relatively low affinity to dopamine D-2 receptors, was hypothe sized to be sensitive to the striatal synaptic dopamine concentration. Syst emic administration of scopolamine at doses of 10 and 100 mu g/kg dose-depe ndently increased both dopamine synthesis and DAT availability as measured by L-[beta-C-11]DOPA and [beta-C-11]CFT, respectively. Scopolamine decrease d the binding of [C-11]raclopride in a dose-dependent manner. Scopolamine i nduced no significant changes in dopamine concentration in the striatal ext racellular 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 [C-11]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 "sta tic" ECF dopamine level but showing a decrease in [C-11]raclopride binding in vivo attributable to the reduction of affinity of dopamine D-2 receptors .