Adenosine receptor–dopamine receptor interactions in the basal ganglia and their relevance for brain function

Abstract

The dopamine D₁ and D₂ receptors are major receptors in the regulation of striatal function and striatal adenosine A₁ and A_2A receptors are major modulators of their signaling. The evidence suggests the existence of antagonistic A₁–D₁ heteromeric receptor complexes in the basal ganglia and prefrontal cortex and especially in the direct striatonigral–striatoentopeduncular GABA pathways. The neurochemical and behavioral findings showing antagonistic A₁–D₁ receptor interactions can be explained by the existence of such A₁–D₁ heteromeric receptor complexes and of antagonistic interactions at the level of the second messengers. In contrast, A_2A–D₂ receptor heteromers may exist in the dorsal and ventral striato-pallidal GABA pathways, where activation of A_2A receptors reduces D₂ receptor recognition, coupling and signaling. As a result of the A_2A receptor-induced reduction of D₂ receptor signaling, the activity of these GABA neurons is increased resulting in reduced motor and reward functions mediated via the indirect pathway, causing a reduced glutamate drive to the prefrontal and motor areas of the cerebral cortex. Thus, A_2A receptor antagonists and A_2A receptor agonists, respectively, may offer novel treatments of Parkinson's disease (reduced D₂ receptor signaling) and of schizophrenia and drug addiction (increased D₂ receptor signaling).

Introduction

There exist two major adenosine–dopamine receptor interactions in the basal ganglia, the antagonistic adenosine A₁–dopamine D₁ receptor interaction in the striatonigral–striatoentopeduncular GABA pathway (direct pathway) and the antagonistic adenosine A_2A–dopamine D₂ receptor interactions in the striato-pallidal GABA pathways (the first neuron in the indirect pathway) (see Refs. [1], [2], [3]). The direct pathway mediates motor activation, while the indirect pathway mediates motor inhibition. The first indication for antagonistic adenosine–dopamine receptor interactions was obtained in behavioral studies in models of Parkinson's disease using unselective adenosine antagonists caffeine and theophyllamine in combination with l-DOPA and dopamine receptor agonists, leading to enhancement of the increases in motor activity produced by the dopaminergic drugs [4].

Among a large number of behavioral studies on adenosine–dopamine receptor interactions since that time a few examples may be given. Thus, the A₁ receptor agonist CPA counteracted the D₁ receptor agonist (SKF 38393)-induced grooming behavior with the A_2A receptor agonist CGS 21680 having no effects [5]. In line with these results, the A₁ receptor antagonist CPT enhanced the motor activating effects of the D₁ agonist SKF 38393 in reserpinized mice and in rat models of Parkinson's disease (unilateral 6-OH-dopamine lesions of the nigrostriatal dopamine pathway) [6]. These behavioral results at the network level indicate the possibility of the existence of antagonistic A₁–D₁ receptor interactions.

Other behavioral results show that low doses of the A_2A receptor agonist CGS 21680 antagonize the D₂-like receptor agonist quinpirole-induced yawning behavior in rats [5]. Furthermore, low doses of CGS 21680 can counteract D₂ but not D₁ receptor agonist-induced increases of motor activity (see Refs. [1], [2]). In line with these results A_2A receptor antagonists markedly enhances the behavioral activation caused by D₂ but not D₁ receptor agonists [1], [2], [7], [8].Thus the behavioral studies also give support for the existence of antagonistic A_2A–D₂ receptor interactions.

In the present review we will summarize the evidence that the existence of striatal A₁–D₁ heteromeric receptor complexes and striatal A_2A–D₂ heteromeric receptor complexes may be the major molecular basis for the observed antagonistic A₁–D₁ and A_2A–D₂ receptor interactions at the behavioral level.