[Microdialysis study of tolcapone effect during blockage of neuronal dopamine reuptake caused by GBR-12909].
In vivo brain functions analysis was conducted to assess the effect of tolcapone, a novel catechol-O-methyltransferase (COMT) inhibitor on extracellular levels of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum of awake, freely moving eats during GBR 12909-induced blockade of DA uptake. Tolcapone administration (30 mg/kg, i.p.) failed to change the dopamine output but caused a marked and long-lasting decrease in the extracellular level of HVA and increase in that of DOPAC. In contrast, injection of the DA uptake inhibitor GBR 12909 directly into the striatum (5 microM) or i.p. (20 mg/kg) led to increase in the DA level but had no significant effect on the metabolites. Co-administration of tolcapone (30 mg/kg i.p.) and CBR 12909 (20 mg/kg) increased the DA level further, whereas the changes in HVA and DOPAC levels remained approximately the same as after injection of tolcapone alone. Behavioral observation showed GBR 12909-induced hyperactivity and stereotypy to be potentiated by tolcapone. These findings show that in the rat striatum under conditions of normal nerve activity DA uptake completely inhibits the increase in striatal DA neurotransmission induced by tolcapone (30 mg/kg i.p.) through COMT inhibition.
Budygin
E A
EA
Institute of Pharmacology, Russian Academy of Medical Sciences, Moscow, Russia.
Gaĭnetdinov
R R
RR
Raevskiĭ
K S
KS
Li
I H
IH
Mannisto
P T
PT
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001577:Benzophenones / Q000494:pharmacology*; D065098:Catechol O-Methyltransferase Inhibitors; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013239:Stereotyped Behavior / Q000187:drug effects; D000077867:Tolcapone
D000978:Antiparkinson Agents; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D018765:Dopamine Uptake Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D010879:Piperazines; D015102:3,4-Dihydroxyphenylacetic Acid; C043425:vanoxerine; D000077867:Tolcapone; D004298:Dopamine; D006719:Homovanillic Acid
Mikrodializnoe izuchenie éffekta tolkapona na fone blokady obratnogo neĭronal'nogo zakhvata dofamina, vyzvannoĭ GBR-12909.