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-D₂ heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A_2A-D₂ 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-D₃ and A_2A-D₄ heteroreceptor complexes as well as higher order A_2A-D₂-mGluR5 and A_2A-D₂-Sigma1R heteroreceptor complexes. The A_2A receptor protomer can likely modulate the function of the D₄ receptors of relevance for understanding cognitive dysfunction in schizophrenia. A_2A-D₂-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-D₂like receptor complexes will be tested in animal models of schizophrenia. A_2A-D₂-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.