Multiple Adenosine-Dopamine (A2A-D2 Like) Heteroreceptor Complexes in the Brain and Their Role in Schizophrenia

In the 1980s and 1990s, the concept was introduced that molecular integration in the Central Nervous System could develop through allosteric receptor–receptor interactions in heteroreceptor complexes presents in neurons. A number of adenosine–dopamine heteroreceptor complexes were identified that lead to the A(2A)-D(2) heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A(2A)-D(2) receptor–receptor interactions and their presence in the ventral striato-pallidal GABA anti-reward neurons leading to reduction of positive symptoms. Other types of adenosine A(2A) heteroreceptor complexes are also discussed in relation to this disease, such as A(2A)-D(3) and A(2A)-D(4) heteroreceptor complexes as well as higher order A(2A)-D(2)-mGluR5 and A(2A)-D(2)-Sigma1R heteroreceptor complexes. The A(2A) receptor protomer can likely modulate the function of the D(4) receptors of relevance for understanding cognitive dysfunction in schizophrenia. A(2A)-D(2)-mGluR5 complex is of interest since upon A(2A)/mGluR5 coactivation they appear to synergize in producing strong inhibition of the D2 receptor protomer. For understanding the future of the schizophrenia treatment, the vulnerability of the current A(2A)-D(2)like receptor complexes will be tested in animal models of schizophrenia. A(2A)-D(2)-Simag1R complexes hold the highest promise through Sigma1R enhancement of inhibition of D2R function. In line with this work, Lara proposed a highly relevant role of adenosine for neurobiology of schizophrenia.