Striatal plasticity at the network level. Focus on adenosine A2A and D2 interactions in models of Parkinson's Disease
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).
References (28)
- et al.
Adenosine-dopamine interactions in the brain
Neuroscience
(1992) - et al.
Integrated events in central dopamine transmission as analyzed at multiple levels. Evidence for intramembrane adenosine A2A /dopamine D2 and adenosine A1/dopamine D1 receptor interactions in the basal ganglia
Brain Res Rev
(1998) - et al.
Coaggregation, cointernalization and codesensitization of adenosine A2A receptors and dopamine D2 receptors
J Biol Chem
(2002) - et al.
Adenosine A2A -dopamine D2 receptor–receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer
J Biol Chem
(2003) - et al.
Neuropeptides, excitatory amino acid and adenosine A2 receptors regulate D2 receptors via intramembrane receptor–receptor interactions. Relevance for Parkinson's disease and schizophrenia
Neurochem Int
(1992) - et al.
Adenosine/dopamine interaction: implications for the treatment of Parkinson's disease
Parkinsonism Relat Disord
(2001) - et al.
Dopamine denervation leads to an increase in the intramembrane interaction between adenosine A2 and dopamine D2 receptors in the neostriatum
Brain Res
(1992) - et al.
Pharmacology of adenosine A2A receptors
Trends Pharmacol Sci
(1996) - et al.
Differential effects of selective adenosine A1 and A2A receptor agonists on dopamine receptor agonist-induced behavioural responses in rats
Eur J Pharmacol
(1998) - et al.
Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia
Trends Neurosci
(1997)
Adenosine A2 receptors modulate haloperidol-induced catalepsy in rats
Eur J Pharmacol
KF17837: a novel selective adenosine A2A receptor antagonist with anticataleptic activity
Eur J Pharmacol
Adenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats
Eur J Pharmacol
Adenosine A2A receptor antagonism increases striatal glutamate outflow in dopamine-denervated rats
Eur J Pharmacol
Cited by (75)
Acute administration of a dopamine D2/D3 receptor agonist alters behavioral and neural parameters in adult zebrafish
2023, Progress in Neuro-Psychopharmacology and Biological PsychiatryAdenosine A<inf>2A</inf>-dopamine D<inf>2</inf> receptor-receptor interaction in neurons and astrocytes: Evidence and perspectives
2020, Progress in Molecular Biology and Translational Science