Gamma-aminobutyric acidA and benzodiazepine receptor alterations in the rat brain after unilateral 6-hydroxydopamine lesions of the medial forebrain bundle.
Gamma-aminobutyric acidA (GABA(A)) and benzodiazepine (BZ) receptors and dopamine uptake sites in 6-hydroxydopamine-treated rat brains were studied by receptor autoradiography using [3H]muscimol, [3H]flunitrazepam and [3H]mazindol binding, respectively. The rats were unilaterally lesioned in the medial forebrain bundle and the brains were analyzed at 1, 2, 4 and 8 weeks post-lesion. Degeneration of the nigrostriatal pathway after 6-hydroxydopamine treatment caused a significant loss of dopamine uptake sites in the ipsilateral striatum and substantia nigra (SN) in the lesioned animals. In the contralateral side, however, dopamine uptake sites showed no significant changes in the brain throughout the experiments. On the other hand, no significant changes in GABA(A) receptors were observed in the brain of both the ipsilateral and contralateral sides during post-lesion. In contrast, BZ receptors were observed significantly increased in the ventromedial part of striatum of the ipsilateral side from 2 to 4 weeks post-lesion. Furthermore, a transient increase in BZ receptors was found in the ipsilateral SN only at 2 weeks post-lesion. In contralateral side, most regions examined showed no significant changes in BZ receptors throughout the experiments except for a transient increase in the SN at 1 week post-lesion. These results demonstrate that 6-hydroxydopamine can cause severe functional damage in dopamine uptake sites in the nigrostriatal pathway. Our results also suggest that the change in BZ receptors is more pronounced than that in GABA(A) receptors in the brain after 6-hydroxydopamine treatment. Furthermore, our findings suggest that the increase in BZ receptors in the brain of 6-hydroxydopamine-treated model may be due to the additional disruption of the nigrostriatal dopamine system. Thus, investigations into possible changes in neurotransmitter receptors other than dopaminergic receptors appear to be important for the elucidation of pathogenesis of Parkinsons disease.
Araki
T
T
Department of Clinical Pharmacology and Therapeutics, Tohoku University Graduate School of Pharmaceutical Science and Medicine, Aoba-yama, Sendai, Japan. tsuaraki@mail.cc.tohoku.ac.jp
Matsubara
M
M
Fujihara
K
K
Kato
H
H
Imai
Y
Y
Itoyama
Y
Y
D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005445:Flunitrazepam; D018755:GABA Agonists; D018757:GABA Modulators; D008297:Male; D008454:Mazindol; D009118:Muscimol; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D013565:Sympatholytics; D014316:Tritium; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D018765:Dopamine Uptake Inhibitors; D018755:GABA Agonists; D018757:GABA Modulators; D011954:Receptors, Dopamine; D011963:Receptors, GABA-A; D013565:Sympatholytics; D014316:Tritium; D009118:Muscimol; D005445:Flunitrazepam; D016627:Oxidopamine; D008454:Mazindol; D004298:Dopamine