Supersensitization of neurochemical responses by L-DOPA and dopamine receptor agonists in the striatum of experimental Parkinson's disease model rats.
We studied the mechanisms of dopamine receptor agonist- and L-DOPA-mediated supersensitization in experimental Parkinson's disease model rats, by measuring in vivo acetylcholine (ACh) release, GTPase activities, and mRNA expression in the striatum of 6-hydroxydopamine-treated rats. D1 agonist (SKF38393) and D2/D3 agonists (bromocriptine and quinpirole) showed more potent stimulation or inhibitions on ACh release in the model rat than in the control. However, quinpirole-evoked stimulation of GTPase activity was enhance in the model rats, compared to the control, while there was no significant enhancement of the bromocriptine-evoked stimulation. On the other hand, L-DOPA at 0.3-10 pM showed a biphasic action including significant inhibition on the GTPase activity in the lesioned striatal membranes, but not in the control. In the RNAase protection assay, neither D1, D2, Gi1 alpha, GoA alpha nor Gs alpha mRNA expression in the model was significantly different from the control. These findings suggest that there is supersensitization of D1 and D2/D3 receptors in the experimental Parkinson's disease model, while the upregulation of their receptors or GTP-binding proteins (G-proteins) to be coupled to their receptors is unlikely involved in major parts of such mechanisms. In addition, the present report provides the first evidence that L-DOPA mediates neurochemical responses in the plasma membranes, possibly through its receptor.
Ueda
H
H
Department of Pharmacology, Yokohama City University School of Medicine, Japan.
Sato
K
K
Okumura
F
F
Inoue
A
A
Nakata
Y
Y
Ozaki
N
N
Yue
J L
JL
Misu
Y
Y
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D012333:RNA, Messenger; D007980:Levodopa; D016627:Oxidopamine; D020558:GTP Phosphohydrolases; D000109:Acetylcholine