New Developments on the Adenosine Mechanisms of the Central Effects of Caffeine and Their Implications for Neuropsychiatric Disorders

Abstract

Recent studies on interactions between striatal adenosine and dopamine and one of its main targets, the adenosine A_2A receptor-dopamine D₂ receptor (A2AR-D2R) heteromer, have provided a better understanding of the mechanisms involved in the psychostimulant effects of caffeine and have brought forward new data on the mechanisms of operation of classical orthosteric ligands within G protein-coupled receptor heteromers. The striatal A2AR-D2R heteromer has a tetrameric structure and forms part of a signaling complex that includes a Gs and a Gi protein and the effector adenyl cyclase (subtype AC5). Another target of caffeine, the adenosine A₁ receptor-dopamine D₁ receptor (A1R-D1R) heteromer, seems to have a very similar structure. Initially suggested to be localized in the striatum, the A1R-D1R heteromer has now been identified in the spinal motoneuron and shown to mediate the spinally generated caffeine-induced locomotion. In this study, we review the recently discovered properties of A2AR-D2R and A1R-D1R heteromers. Our studies demonstrate that these complexes are a necessary condition to sustain the canonical antagonistic interaction between a Gs-coupled receptor (A2AR or D1R) and a Gi-coupled receptor (D2R or A1R) at the adenylyl cyclase level, which constitutes a new concept in the field of G protein-coupled receptor physiology and pharmacology. A2AR antagonists targeting the striatal A2AR-D2R heteromer are already being considered as therapeutic agents in Parkinson's disease. In this study, we review the preclinical evidence that indicates that caffeine and A2AR antagonists could be used to treat the motivational symptoms of depression and attention-deficit/hyperactivity disorder, while A1R antagonists selectively targeting the spinal A1R-D1R heteromer could be used in the recovery of spinal cord injury.

Keywords: GPCR heteromers; adenosine receptors; attention-deficit/hyperactivity disorder; caffeine; depression; dopamine receptors; spinal cord; spinal cord injury; striatum.

FIG. 1.

The A2AR–D2R heterotetramer–AC5 complex. Schematic slice-representation, viewed from the extracellular side, of the minimal functional unit of the A2AR–D2R heterotetramer in complex with Gs (more specifically Golf) and Gi proteins and adenyl cyclase (subtype AC5), in the absence (A) and presence (B) of A2AR and D2R agonists, which induce a rearrangement of the heterotetramer–AC5 interfaces (modified from Ferré et al.). A2AR–D2R, adenosine A_2A receptor–dopamine D₂ receptor.