Effects of single and repeated administration of 1,2,3,4-tetrahydroisoquinoline analogs on the binding of [11C]raclopride to dopamine D2 receptors in the mouse brain.
We investigated the effects of intraperitoneal injection of 1,2,3,4-tetrahydroisoquinoline (TIQ) analogs and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the binding of [11C]raclopride to striatal dopamine D2 receptors in mice. The binding of [11C]raclopride, but not of [11C]N-methylspiperone or [11C]nemonapride with higher affinity, to the receptors was significantly decreased immediately after TIQ injection. Neither a dopamine transporter blocker induced such effect nor TIQ affected the dopamine transporter-radioligand binding. Among the compounds investigated, including parkinsonism-inducing TIQ and (R/S)-1-benzyl-TIQ, parkinsonism-preventing (R)- and (S)-1-methyl-TIQ, and probable N-methylated metabolites of TIQ and 1-methyl-TIQ, TIQ and (S)-1-methyl-TIQ had the strongest effect on the binding of [11C]raclopride, and N-methylated derivatives showed less of an effect than the respective parent compounds. The decrease in the binding of [11C]raclopride continued for 7 hours and was followed by an increase until 10 days after the single and subchronic administration of TIQ. These findings suggest that TIQ analogs profoundly stimulated dopamine release which resulted in the competitive inhibition of the binding of [11C]raclopride to dopamine D2 receptors, but did not induce degeneration of the receptors.
Ishiwata
K
K
Positron Medical Center, Tokyo Metropolitan Institute of Gerontology, Itabashi, Japan. ishiwata@pet.tmig.or.jp
Koyanagi
Y
Y
Saitoh
T
T
Taguchi
K
K
Toda
J
J
Sano
T
T
Senda
M
M
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000008:administration & dosage; D018492:Dopamine Antagonists / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D051379:Mice; D009498:Neurotoxins / Q000008:administration & dosage* / Q000737:chemistry; D020891:Raclopride / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D044005:Tetrahydroisoquinolines
D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists; D007546:Isoquinolines; D009498:Neurotoxins; D017448:Receptors, Dopamine D2; D044005:Tetrahydroisoquinolines; D020891:Raclopride; C014843:1,2,3,4-tetrahydroisoquinoline