Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson's Disease

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Abstract

Behavioral and microdialysis studies have been performed on antagonistic A2A/D2 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 A2A and/or D2 agonists via reverse microdialysis.

The results show that the A2A 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 D2 like agonist quinpirole. Furthermore, antagonizing the A2A receptor (R) reduced haloperidol induced catalepsy. The behavioral results underline the view that A2A antagonists act by blocking A2A R in A2A/D2 heterodimers where A2A R inhibits the D2 R transduction and D2 inhibits the adenylate cyclase (AC) activated by A2A R.

The microdialysis studies show that the A2A agonist CGS21680 striatally coperfused with the D2 agonist quinpirole more potently counteract the D2 agonist (quinpirole) induced reduction of pallidal glutamate levels in the DA denervated vs the control striatum indicating an enhancement of the inhibitory A2A/D2 interaction. In the DA denervated but not in the control striatum the A2A agonist CGS21680 could strongly increase striatal glutamate levels, indicating an increased receptor signaling in the A2A R located on the striatal glutamate terminals, where also D2 like R exist, here probably as D4. Thus, the signaling of this A2A R may be set free by the loss of D4 tone on the AC activated by A2A in this postulated A2A/D4 heteromer on the glutamate terminals.

Taken together, the results indicate that the antiparkinsonian actions of A2A antagonists probably are produced by blockade of A2A R in the A2A/D2 heterodimers mainly located in the striatopallidal GABA neurons.

Introduction

A large number of studies have indicated that the major action of A2A antagonists in rodent models of Parkinson's Disease is the enhancement of the antiparkinson actions of l-DOPA and D2 agonists [1], [2], [3] The changes in the activity of the basal ganglia in Parkinson's Disease (‘no go’) versus normal (‘go’) are outlined in Fig. 1. It seems likely that the mechanism for these interactions at the behavioral level is the existence of A2A/D2 heterodimers in the somatodendritic region of the striatopallidal GABA neurons where the A2A receptors antagonize the D2 signaling [4], [5], [6], [7]. Based on experiments of this type it has been suggested that A2A antagonists may represent a new type of antiparkinson drugs [3], [6], [7], [8], [9], [10], [11].

In the present paper the analysis of A2A/D2 interaction has been continued in models of Parkinson's Disease using behavioral and microdialysis approaches, involving especially the Ungerstedt model [12] involving unilateral 6-OHDA lesions of the ascending DA pathways. The behavioral studies with subthreshold doses of l-DOPA and D2 agonists give further evidence for the role of A2A receptors (R) as inhibitory modulators of D2 signaling and this mechanism appears to be more potent in the DA denervated striatum as shown in the present dual probe microdialysis studies in line with previous in vitro findings [13].

Section snippets

Animals

All experimental procedures carried out in this study were in complicance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and approved by the Danish animal welfare committee, appointed by the Danisk Ministry of Justice. For the locomotor activity studies, female NMRI mice were used (Taconic MandB, P. O. Box 1079, DK-8680 Ry, Denmark). For the unilateral 6-OHDA lesions and haloperidol-induced catalepsia, male Wistar rats were used (Taconic MandB, P. O. Box 1079,

Locomotor activity in reserpinized mice

Systemic administration of reserpine in mice depletes the catecholamines dopamine and noradrenaline and results in marked hypoactivity. The parameter measured is number of photocell interruptions in automated motility cages. The A2A antagonist SCH58261 showed a dose-dependent increase in locomotor activity in reserpinized mice administered a subthreshold dose of l-DOPA (Fig. 2). There was no effect of the A2A antagonist, SCH58261 in reserpinized mice tested without a subthreshold dose of l

Discussion

The behavioral experiments with the effects of A2A R antagonists on locomotion in reserpinized mice and on contralateral rotational behaviors in 6-OHDA lesioned rats emphasize the need of giving subthreshold doses of l-DOPA and D2 like agonists in order to see increases in motor behaviors with the A2A antagonists tested. These results strongly support the view that A2A antagonists mainly act by enhancing D2 signaling, presumably in the A2A/D2 heterodimer [1], [2], [6], [9], [15], [16]

These

Acknowledgements

This work has been supported by a grant from EC (QLG3-CT2001-01056) and the Swedish Research Council (04X-715).

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