Borroto-Escuela, Dasiel O.Ferraro, LucaNarvaez, ManuelTanganelli, SergioBeggiato, SarahLiu, FangRivera, AliciaFuxe, Kjell2024-02-122024-02-122020-04-27http://hdl.handle.net/10668/3840http://hdl.handle.net/20.500.12105/18037In 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 A2A-D2 heteromer hypothesis of schizophrenia. The hypothesis is based on strong antagonistic A2A-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 A2A heteroreceptor complexes are also discussed in relation to this disease, such as A2A-D3 and A2A-D4 heteroreceptor complexes as well as higher order A2A-D2-mGluR5 and A2A-D2-Sigma1R heteroreceptor complexes. The A2A receptor protomer can likely modulate the function of the D4 receptors of relevance for understanding cognitive dysfunction in schizophrenia. A2A-D2-mGluR5 complex is of interest since upon A2A/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 A2A-D2like receptor complexes will be tested in animal models of schizophrenia. A2A-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.engVoRhttp://creativecommons.org/licenses/by/4.0/Adenosine receptorsA2A-D2 heteroreceptor complexesSchizophreniaBrainNovel pharmacologyHeterobivalent drugsSigma 1 receptorReceptor de adenosina A2AEsquizofreniaEncéfaloFarmacologíaProteínas del núcleo viralReceptor, Adenosine A2ABrainCentral Nervous SystemDopamineHumansNeuronsReceptors, Dopamine D2SchizophreniaAttribution 4.0 International3234927910.3390/cells90510772073-4409Cellsopen access