Abstract
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.