Electrophysiological and behavioural evidence for an antagonistic modulatory role of adenosine A2A receptors in dopamine D2 receptor regulation in the rat dopamine-denervated striatum.
It has been shown that striatal adenosine A2A receptors can antagonistically interact with dopamine D2 receptors at the membrane level leading to a decrease in the affinity and efficacy of D2 receptors. Extracellular recordings and rotational behaviour were employed to obtain a correlate to these findings in an animal model of Parkinson's disease (PD). The recordings were performed in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced catecholamine depletion. While recording in the dopamine-depleted striatum, local applications of the dopamine D2 agonist quinpirole reduced neuronal activity. However, when the adenosine A2A antagonist MSX-3 was applied simultaneously with quinpirole, the inhibition of neuronal firing seen after quinpirole alone was significantly potentiated (P< 0.001, n = 11). In contrast, local application of CGS 21680 attenuated the effect of quinpirole. The doses of MSX-3 and CGS 21680 used to achieve the modulation of quinpirole action had no effect per se on striatal neuronal firing. Furthermore, rotational behaviour revealed that MSX-3 dose-dependently increased the number of turns when administrated together with a threshold dose of quinpirole while no enhancement was achieved when MSX-3 was combined with SKF 38393. MSX-3 alone did not induce rotational behaviour. In conclusion, this study shows that low ineffective doses of MSX-3 enhance the effect of quinpirole on striatal firing rate, while the A2A agonist exerts the opposite action. This mechanism gives a therapeutic potential to A2A antagonists in the treatment of PD by enhancing D2 receptor function.
Strömberg
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Department of Neuroscience, Karolinska Institute, Stockholm, S-17177 Sweden. ingrid.stromberg@neuro.ki.se
Popoli
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Müller
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Ferré
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D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D003714:Denervation; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D007839:Functional Laterality; D006801:Humans; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000503:physiopathology; D010627:Phenethylamines / Q000494:pharmacology; D058915:Purinergic P1 Receptor Antagonists; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D012016:Reference Values
D010627:Phenethylamines; D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019257:Quinpirole; D016627:Oxidopamine; D000241:Adenosine; D004298:Dopamine