Adenosine A(2A) receptor-mediated modulation of GABA and glutamate release in the output regions of the basal ganglia in a rodent model of Parkinson's disease.
A target neuron of adenosine A(2A) receptor antagonists to exert anti-parkinsonian activities has been currently identified to be, at least in part, striatopallidal medium spiny neurons (MSNs). In the present study, we determine whether A(2A) receptor-mediated modulation is associated with changes in the release of GABA and glutamate in the substantia nigra pars reticulata (SNr), an output structure of the whole basal ganglia network, using in vivo microdialysis in a rat Parkinson's disease (PD) model. In 6-hydroxydopamine (OHDA)-lesioned rats compared with normal rats, basal extracellular GABA levels in the SNr show no change, whereas basal glutamate levels are significantly increased. Oral administration of the A(2A) receptor-selective antagonist (E-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1-H-purine-2,6-dion (KW-6002) to 6-OHDA-lesioned rats at 1 mg/kg caused a marked and sustained increase of GABA and glutamate levels in the SNr. The increase of nigral glutamate by KW-6002 was abolished by a kainic acid-induced lesion of the globus pallidus (GP) or subthalamic nucleus (STN) in 6-OHDA-lesioned rats, whereas the increase of nigral GABA was completely blocked by the GP-lesion but only partially blocked by the STN-lesion. These results indicate that changes in neurotransmitter release in the SNr brought about by KW-6002 are largely attributable to blockade of A(2A) receptor-mediated modulation of striatopallidal MSNs. Thus, these actions of KW-6002 on striatopallidal MSNs may be the main mechanism for ameliorating PD by A(2A) antagonists.
Ochi
M
M
Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd, Nagaizumi, Sunto, Shizuoka 411-8731, Japan.
Shiozaki
S
S
Kase
H
H
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001479:Basal Ganglia / Q000378:metabolism* / Q000503:physiopathology; D003714:Denervation; D004195:Disease Models, Animal; D004525:Efferent Pathways / Q000378:metabolism* / Q000503:physiopathology; D045604:Extracellular Fluid / Q000378:metabolism; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D008959:Models, Neurological; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine