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

Cells. 2020 Apr 27;9(5):1077. doi: 10.3390/cells9051077.


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 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.

Keywords: A2A-D2 heteroreceptor complexes; adenosine receptors; brain; heterobivalent drugs; novel pharmacology; schizophrenia; sigma 1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Adenosine / metabolism
  • Brain / metabolism
  • Central Nervous System / metabolism
  • Dopamine / metabolism
  • Humans
  • Neurons / metabolism
  • Receptor, Adenosine A2A / metabolism*
  • Receptor, Adenosine A2A / physiology
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D2 / physiology
  • Schizophrenia / metabolism*
  • Schizophrenia / physiopathology


  • Receptor, Adenosine A2A
  • Receptors, Dopamine D2
  • Adenosine
  • Dopamine