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The Journal of Neuroscience, September 15, 2000, 20(18):7067-7073

Cholinergic Neuronal Modulation Alters Dopamine D₂ 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

Hideo Tsukada, Norihiro Harada, Shingo Nishiyama, Hiroyuki Ohba, and Takeharu Kakiuchi

Central Research Laboratory, Hamamatsu Photonics K. K., Shizuoka 434-8601, Japan

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-[-¹¹C]DOPA) and 2-carbomethoxy-3-(4-fluorophenyl)tropane ([-¹¹C]CFT) were used to measure dopamine synthesis rate and dopamine transporter (DAT) availability, respectively. For assessment of dopamine D₂ receptor binding in vivo, [¹¹C]raclopride was applied because this labeled compound, which has relatively low affinity to dopamine D₂ receptors, was hypothesized to be sensitive to the striatal synaptic dopamine concentration. Systemic administration of scopolamine at doses of 10 and 100 µg/kg dose-dependently increased both dopamine synthesis and DAT availability as measured by L-[-¹¹C]DOPA and [-¹¹C]CFT, respectively. Scopolamine decreased the binding of [¹¹C]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 [¹¹C]raclopride revealed that scopolamine reduced the apparent affinity of dopamine D₂ 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 [¹¹C]raclopride binding in vivo attributable to the reduction of affinity of dopamine D₂ receptors.

Key words: L-[-¹¹C]DOPA; [¹¹C]raclopride; [-¹¹C]CFT; positron emission tomography; microdialysis; monkey brain

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20187067-07$05.00/0

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