Intrapallidal metabotropic glutamate receptor activation in a rat model of Parkinson's disease: behavioral and histological analyses.
Metabotropic glutamate receptors (mGluRs) have been recently implicated as robust therapeutic targets for Parkinson's disease (PD). Here, we explored how activation of mGluRs in globus pallidus (GP) affected the amphetamine-induced rotational behavior in the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of PD. The amphetamine-induced rotations were completely suppressed by the ipsilateral intrapallidal injection of the non-selective mGluR agonist, 1-aminocyclopentane-1S,3R-dicarboxylic acid (ACPD) and the selective group I mGluR agonist, (R,S)-3,5-dihydroxyphenylglycine (DHPG), but not the selective group III mGluR agonist, l-2-amino-4-phosphonobutyric acid (l-AP4). The suppressive effects were detected at 2, 4, 6, 8, and 12 h after ACPD injection, but returned to the control level at 24 h. A remarkable c-fos expression was found in the lesioned side of GP, subthalamic nucleus (STN), and substantia nigra pars reticulata (SNr) of rats that received the ACPD or DHPG injection, compared to rats treated with L-AP-4 or phosphate buffer-injection. The results indicate that the blockade of amphetamine-induced rotations might be at least partially mediated by group I mGluR activation. This study advances the use of selective group I mGluRs directed toward the GP for PD treatment.
Agari
Takashi
T
Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama, Japan, 700-8558.
Yasuhara
Takao
T
Matsui
Toshihiro
T
Kuramoto
Satoshi
S
Kondo
Akihiko
A
Miyoshi
Yasuyuki
Y
Shingo
Tetsuro
T
Borlongan
Cesario V
CV
Date
Isao
I
D018663:Adrenergic Agents / Q000633:toxicity; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D004148:Dioxolanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D005917:Globus Pallidus / Q000378:metabolism*; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018663:Adrenergic Agents; D004148:Dioxolanes; D018691:Excitatory Amino Acid Antagonists; D016760:Proto-Oncogene Proteins c-fos; D011687:Purines; D018094:Receptors, Metabotropic Glutamate; C104068:4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol; D008734:Methoxyhydroxyphenylglycol; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; C010117:3,4-dihydroxyphenylglycol