| Summary: | 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<sub>2A</sub>-D<sub>2</sub> heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A<sub>2A</sub>-D<sub>2</sub> 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<sub>2A</sub> heteroreceptor complexes are also discussed in relation to this disease, such as A<sub>2A</sub>-D<sub>3</sub> and A<sub>2A</sub>-D<sub>4</sub> heteroreceptor complexes as well as higher order A<sub>2A</sub>-D<sub>2</sub>-mGluR5 and A<sub>2A</sub>-D<sub>2</sub>-Sigma1R heteroreceptor complexes. The A<sub>2A</sub> receptor protomer can likely modulate the function of the D<sub>4</sub> receptors of relevance for understanding cognitive dysfunction in schizophrenia. A<sub>2A</sub>-D<sub>2</sub>-mGluR5 complex is of interest since upon A<sub>2A</sub>/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<sub>2A</sub>-D<sub>2</sub>like receptor complexes will be tested in animal models of schizophrenia. A<sub>2A</sub>-D<sub>2</sub>-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.
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