Facilitation of dopaminergic neural transmission does not affect [(11)C]SCH23390 binding to the striatal D(1) dopamine receptors, but the facilitation enhances phosphodiesterase type-IV activity through D(1) receptors: PET studies in the conscious monkey brain.
The present study evaluated the effects of methamphetamine and scopolamine on the striatal dopamine D(1) receptor binding, measured by [(11)C]SCH23390, and D(1) receptor-coupled cAMP messenger system, determined as phosphodiesterase type-IV (PDE-IV) activity, were evaluated in the brains of conscious monkeys using positron emission tomography (PET) with microdialysis. When methamphetamine (0.1, 0.3, and 1 mg/kg) or scopolamine (0.01, 0.03, and 0.1 mg/kg) was systemically administered, [(11)C]SCH23390 binding to D(1) receptors was not affected. With administration of methamphetamine, the striatal PDE-IV activity, as measured with R-[(11)C]rolipram (active form) and S-[(11)C]rolipram (inactive form), was dose-dependently facilitated with enhanced dopamine level in the striatal ECF. Administration of scopolamine also induced facilitated PDE-IV activity without any apparent changes in the ECF dopamine. These facilitations of PDE-IV activity were abolished by preadministration of SCH23390, but not by raclopride. These results demonstrate that, as evaluated by PDE-IV activity, the inhibition of muscarinic cholinergic receptors actually facilitated dopamine neuronal signal transduction through D(1) receptors, as observed previously on D(2) receptors with no apparent increase in the striatal ECF dopamine level, but the enhanced dopamine transmission could not detected by [(11)C]SCH23390.
Tsukada
H
H
Central Research Laboratory, Hamamatsu Photonics K.K., Shizuoka 434-8601, Japan. tsukada@crl.hpk.co.jp
Harada
N
N
Ohba
H
H
Nishiyama
S
S
Kakiuchi
T
T
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism*; D000818:Animals; D001552:Benzazepines / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000493:pharmacokinetics; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D020889:Rolipram / Q000493:pharmacokinetics; D012601:Scopolamine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000502:physiology*; D014055:Tomography, Emission-Computed
D001552:Benzazepines; D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D010726:Phosphodiesterase Inhibitors; D017447:Receptors, Dopamine D1; D008694:Methamphetamine; D012601:Scopolamine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D004298:Dopamine