Decreased striatal adenosine A2A-dopamine D2 receptor heteromerization in schizophrenia

Abstract

According to the adenosine hypothesis of schizophrenia, the classically associated hyperdopaminergic state may be secondary to a loss of function of the adenosinergic system. Such a hypoadenosinergic state might either be due to a reduction of the extracellular levels of adenosine or alterations in the density of adenosine A 2A receptors (A 2A Rs) or their degree of functional heteromerization with dopamine D 2 receptors (D 2 R). In the present study, we provide preclinical and clinical evidences for this latter mechanism. Two animal models for the study of schizophrenia endophenotypes, namely the phencyclidine (PCP) mouse model and the A 2A R knockout mice, were used to establish correlations between behavioral and molecular studies. In addition, a new AlphaLISA-based method was implemented to detect native A 2A R-D 2 R heteromers in mouse and human brain. First, we observed a reduction of prepulse inhibition in A 2A R knockout mice, similar to that observed in the PCP animal model of sensory gating impairment of schizophrenia, as well as a significant upregulation of striatal D 2 R without changes in A 2A R expression in PCP-treated animals. In addition, PCP-treated animals showed a significant reduction of striatal A 2A R-D 2 R heteromers, as demonstrated by the AlphaLISA-based method. A significant and pronounced reduction of A 2A R-D 2 R heteromers was next demonstrated in post-mortem caudate nucleus from schizophrenic subjects, even though both D 2 R and A 2A R were upregulated. Finally, in PCP-treated animals, sub-chronic administration of haloperidol or clozapine counteracted the reduction of striatal A 2A R-D 2 R heteromers. The degree of A 2A R-D 2 R heteromer formation in schizophrenia might constitute a hallmark of the illness which indeed should be further studied to stablish possible correlations with chronic antipsychotic treatments.

Dopamine Activates Astrocytes in Prefrontal Cortex via α1-Adrenergic Receptors

“…While radioligand binding studies indicate that non-specific interaction of DA with α1-AR only occurs at sub-millimolar concentrations (Proudman and Baker, 2021; Steinberg and Bilezikian, 1982) (much higher than those used in the present experiments), D1 and α1AR colocalize on PFC dendrites and have been suggested to undergo co-trafficking (Mitrano et al, 2014). In addition, mounting evidence from co-immunoprecipitation, BRET/FRET sensors and proximity-ligation assays support the idea that DRs can form functional heteromeric complexes with ARs and other class A GPCRs (Azdad et al, 2009; Bonaventura et al, 2014; González et al, 2012; Kolasa et al, 2018; Lee et al, 2004; Moreno et al, 2014; Navarro et al, 2018; Pelassa et al, 2019; Rebois et al, 2012; Trifilieff et al, 2011; Valle-León et al, 2021; Zhu et al, 2020), although evidence against the existence of DR heteromers in vivo also exists (Frederick et al, 2015).…”

Heterobivalent Ligand for the Adenosine A2A–Dopamine D2 Receptor Heteromer

“…A 2A R−D 2 R heteromers have been found in transfected cells, 26 in native tissue, 27 and in human postmortem brains in which the amount of heteromer differs from healthy and diseased, increasing in Parkinson's disease 28 and decreasing in schizophrenia. 29 In fact, the dopamine precursor L-DOPA is used in combination with the selective A 2A R antagonist istradefylline (marketed as Nouriast in Japan in 2013 and as Nourianz in the United States in 2019) for the treatment of Parkinson's disease to abolish the negative allosteric modulation of A 2A R on D 2 R. 30 Other published approaches to target the A 2A R−D 2 R heteromer have consisted of the development of dual-target bitopic ligands 31 and bivalent ligands. 32 A major focus has been on the generation of heteromerselective tools that recognize oligomers in native tissues.…”

“…This is of interest in the pharmaceutical context as changes in the A 2A R−D 2 R heteromer population have been observed in pathological conditions such as Parkinson's disease 28 and schizophrenia. 29…”

Adenosine A2A receptor in schizophrenia: an in vivo brain PET imaging study

“…Changes in the degree of A2AR-D2R heteromerization could potentially counteract changes in A2A receptor levels. (Valle-León et al 2021). Future studies should contribute to elucidate the close relationship between the expression of A2A and D2 receptor expression and A2A-D2 heteromers.…”