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.