Systemic administration of adenosine A(2A) receptor antagonist reverses increased GABA release in the globus pallidus of unilateral 6-hydroxydopamine-lesioned rats: a microdialysis study.
The ability of adenosine A(2A) receptor antagonists to exhibit antiparkinsonian activity has recently been reported, but the mechanisms of action are still unknown. Since A(2A) receptors have been localized to GABAergic striatopallidal neurons, it is probable that these antagonists affect the activity of these neurons. In the present study, extracellular GABA basal levels were increased in the ipsilateral striatum and globus pallidus following a unilateral 6-hydroxydopamine lesion of the nigrostriatal pathway. The A(2A) receptor-selective antagonist KW-6002 (3mg/kg, p.o.) caused a marked and sustained decrease of extracellular GABA levels in the globus pallidus of the 6-hydroxydopamine-lesioned rats, whereas no changes in GABA levels were observed in the globus pallidus of the non-lesioned rats. Microinjection of the A(2A) receptor agonist CGS21680 (0.005-0.5 microg) into the striatum of non-lesioned animals increased GABA concentrations in the globus pallidus, which was abolished by the voltage-dependent Na(+) channel blocker tetrodotoxin (1 micromol/l) delivered locally to the globus pallidus via the dialysis membrane. Furthermore, intrapallidal infusion of CGS21680 (10 micromol/l) also increased GABA levels in the globus pallidus. These data indicate that GABA release from striatopallidal neurons is regulated through A(2A) receptors in both the striatum and globus pallidus. The reversal of the 6-hydroxydopamine-induced increase in pallidal GABA levels by KW-6002 suggests that the antiparkinsonian effects of A(2A) receptor antagonists occur on the striatopallidal neurons.
Ochi
M
M
Pharmaceutical Research Institute, Kyowa Hakko Kogyo, Nagaizumi, Sunto, 411-8731, Shizuoka, Japan.
Koga
K
K
Kurokawa
M
M
Kase
H
H
Nakamura
J
J
Kuwana
Y
Y
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D018756:GABA Antagonists / Q000494:pharmacology*; D005917:Globus Pallidus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008845:Microinjections; D016627:Oxidopamine / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D018756:GABA Antagonists; D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C111599:istradefylline; D005680:gamma-Aminobutyric Acid; D016627:Oxidopamine; D000241:Adenosine