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.
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-[beta-(11)C]DOPA) and 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane ([beta-(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 microg/kg dose-dependently increased both dopamine synthesis and DAT availability as measured by l-[beta-(11)C]DOPA and [beta-(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.
Tsukada
H
H
Central Research Laboratory, Hamamatsu Photonics K. K., Shizuoka 434-8601, Japan. tsukada@crl.hpk.co.jp
Harada
N
N
Nishiyama
S
S
Ohba
H
H
Kakiuchi
T
T
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002250:Carbon Radioisotopes; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002799:Cholinergic Fibers / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D004295:Dihydroxyphenylalanine / Q000493:pharmacokinetics; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017551:Microdialysis; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage; D020891:Raclopride / Q000493:pharmacokinetics; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D013569:Synapses / Q000378:metabolism*; D014055:Tomography, Emission-Computed; D014851:Wakefulness / Q000502:physiology
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D018727:Muscarinic Antagonists; D009419:Nerve Tissue Proteins; D010879:Piperazines; D017448:Receptors, Dopamine D2; D020891:Raclopride; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D004295:Dihydroxyphenylalanine; C043425:vanoxerine; D012601:Scopolamine; D003042:Cocaine; D004298:Dopamine