Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson's Disease.
Behavioral and microdialysis studies have been performed on antagonistic A(2A)/D(2) interactions in animal models of Parkinson's Disease. The behavioral analysis involved studies on locomotor activity in reserpinized mice, haloperidol-induced catalepsy in rats and rotational behavior in rats with unilateral 6-OHDA lesions of the ascending DA pathways (Ungerstedt model). Dual probe microdialysis studies were indirectly performed on the striatopallidal GABA neurons by studying extracellular glutamate levels in the striatum and globus pallidus of the awake freely moving rat. The striatum was perfused with A(2A) and/or D(2) agonists via reverse microdialysis. The results show that the A(2A) antagonists SCH58261 and KF17837 can increase locomotor activity in reserpinized mice and produce contralateral rotational behavior only after administration of subthreshold doses of l-DOPA or the D(2) like agonist quinpirole. Furthermore, antagonizing the A(2A) receptor (R) reduced haloperidol induced catalepsy. The behavioral results underline the view that A(2A) antagonists act by blocking A(2A) R in A(2A)/D(2) heterodimers where A(2A) R inhibits the D(2) R transduction and D(2) inhibits the adenylate cyclase (AC) activated by A(2A) R. The microdialysis studies show that the A(2A) agonist CGS21680 striatally coperfused with the D(2) agonist quinpirole more potently counteract the D(2) agonist (quinpirole) induced reduction of pallidal glutamate levels in the DA denervated vs the control striatum indicating an enhancement of the inhibitory A(2A)/D(2) interaction. In the DA denervated but not in the control striatum the A(2A) agonist CGS21680 could strongly increase striatal glutamate levels, indicating an increased receptor signaling in the A(2A) R located on the striatal glutamate terminals, where also D(2) like R exist, here probably as D(4). Thus, the signaling of this A(2A) R may be set free by the loss of D(4) tone on the AC activated by A(2A) in this postulated A(2A)/D(4) heteromer on the glutamate terminals. Taken together, the results indicate that the antiparkinsonian actions of A(2A) antagonists probably are produced by blockade of A(2A) R in the A(2A)/D(2) heterodimers mainly located in the striatopallidal GABA neurons.
Tanganelli
S
S
Department of Clinical and Experimental Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Sandager Nielsen
K
K
Ferraro
L
L
Antonelli
T
T
Kehr
J
J
Franco
R
R
Ferré
S
S
Agnati
L F
LF
Fuxe
K
K
Scheel-Krüger
J
J
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D005260:Female; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D051379:Mice; D009415:Nerve Net / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D065127:Dopamine D2 Receptor Antagonists; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D014230:Triazoles; D007980:Levodopa