Adenosine–Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders

Abstract

Adenosine-dopamine interactions in the central nervous system (CNS) have been studied for many years in view of their relevance for disorders of the CNS and their treatments. The discovery of adenosine and dopamine receptor containing receptor mosaics (RM, higher-order receptor heteromers) in the striatum opened up a new understanding of these interactions. RM have been discovered using a sequential BRET-FRET technique and by using the BRET technique in combination with bimolecular fluorescence complementation. Thus, other pathogenic mechanisms beside the well-known alterations in the release and/or decoding of dopamine in the basal ganglia and limbic system are involved in PD, schizophrenia and drug addiction. In fact, alterations in the stoichiometry and/or topology of A 2A -CB 1 -D 2 and A 2A -D 2 -mGlu5 RM may play a role. Thus, the integrative receptor-receptor interactions in these RM give novel aspects on the pathophysiology and treatment strategies, based on combined treatments, for PD, schizophrenia, and drug addiction.

Adenosine Signaling in Striatal Circuits and Alcohol Use Disorders

“…A2AR agonists are known to cause a conformational change in the shape of D2R, which in turn, leads to a reduction in dopamine binding to D2R, and thus prevents the effects of D2R signaling, such as phosphorylation of Ca 2+ ion channels. Furthermore, A2AR agonism (as well as D2 antagonism) has been shown to increase the expression of c-fos (Fuxe et al, 2010) and inhibit the release of GABA. In contrast, D2R agonists and A2AR antagonists have the reverse effect and inhibit c-fos expression (Ferré et al, 1997;Fuxe et al, 2007;2010).…”

“…Interestingly, A2AR agonists are able to diminish the rewarding effects of cocaine, and counteract the sensitization to the locomotor effects of cocaine. Furthermore, A2AR antagonists have also been associated with reinstatement of cocaine self-administration, implying that the A2AR plays an important role in the mechanisms of addiction (Fuxe et al, 2010).…”

“…A1R agonists have been found to significantly decrease the binding affinity of D1R located in the NAc and the PFC (Fuxe et al, 2010). This suggests that, similar to A2AR-D2R heterodimers, a conformational change in the structure of the D1R is caused by adenosine binding to the A1R, and thus, decreases dopamine signaling.…”

“…This suggests that, similar to A2AR-D2R heterodimers, a conformational change in the structure of the D1R is caused by adenosine binding to the A1R, and thus, decreases dopamine signaling. In contrast, A1R antagonists have been shown to have the reverse effect and increase dopaminergic signaling (Fuxe et al, 2010). Furthermore, A1R agonists have also demonstrated an ability to counteract the effects of D1R activation, indicating that the function of A1R in the A1R-D1R heterodimer is to inhibit dopamine signaling via the D1R.…”

Phasic D1 and tonic D2 dopamine receptor signaling double dissociate the motivational effects of acute nicotine and chronic nicotine withdrawal

“…In the striatum, adenosine A2A receptors (A2ARs) and D2Rs are colocalized (29) and form A2AR-D2R heteromers (30). The A2AR and D2R interact antagonistically, such that agonism of A2ARs decreases signaling at D2Rs (31) and antagonism of A2ARs increases signaling at D2Rs (30).…”