Sequential changes of dopaminergic receptors in the rat brain after 6-hydroxydopamine lesions of the medial forebrain bundle.
We investigated the sequential patterns of changes in dopamine uptake sites, D1 and D2 receptors in the brain of animals lesioned with 6-hydroxydopamine using quantitative receptor autoradiography. The rats were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks postlesion. Degeneration of the nigrostriatal pathway caused a significant loss of dopamine uptake sites in the ipsilateral striatum, substantia nigra (SN) and ventral tegmental area (VTA) in the lesioned animals. Dopamine D1 receptors were significantly increased in the ventromedial part of striatum of the ipsilateral side from 2 to 4 weeks postlesion. In the ipsilateral SN, a transient increase in dopamine D1 receptors was observed only 1 week after lesioning. However, the frontal cortex, parietal cortex and dorsolateral part of the striatum showed no significant change in dopamine D1 receptors throughout the experiments. On the other hand, dopamine D2 receptors were decreased increased in the ipsilateral SN and VTA from 1 week to 8 weeks postlesion. In the ipsilateral striatum, dopamine D2 receptors were increased in the dorsolateral part from 2 weeks to 8 weeks and in the ventromedial part from 2 weeks to 4 weeks. However, the frontal cortex and parietal cortex showed no significant change in dopamine D2 receptors during postlesion. In the contralateral side, most of regions examined showed no significant change in dopamine uptake sites, dopamine D1 receptors and dopamine D2 receptors during postlesion except for a transient change in a few regions. These results demonstrate that 6-hydroxydopamine can cause a severe functional damage in dopamine uptake sites in the striatum, SN and VTA. Our findings also suggest that the up-regulation in dopamine D2 receptors is more pronounced than that in dopamine D1 receptors in the brain after 6-hydroxydopamine treatment. Furthermore, our results support the existence of dopamine D2 receptors on the neurons of SN and VTA. Thus, our findings provide insights into the pathogenesis of Parkinson's disease.
Araki
T
T
Department of Neurology, Tohoku University School of Medicine, Sendai, Japan.
Tanji
H
H
Kato
H
H
Itoyama
Y
Y
D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000378:metabolism; D001552:Benzazepines / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D008297:Male; D008454:Mazindol / Q000378:metabolism; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000473:pathology; D016627:Oxidopamine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013997:Time Factors
D018663:Adrenergic Agents; D001549:Benzamides; D001552:Benzazepines; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016627:Oxidopamine; D008454:Mazindol; C030265:nemonapride; D004298:Dopamine