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 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.
Highlights
The concept was developed in the 1990s that the communication in the central dopamine neurons could become integrated with adenosine communication through the formation of heteroreceptor complexes built up of adenosine and dopamine receptors in a receptor subtype specific way locatedCells 2020, 9, 1077; doi:10.3390/cells9051077 www.mdpi.com/journal/cellsCells 2020, 9, 1077 in the plasma membrane, specially extrasynaptic regions [1]
It was of high interest that the A2A receptor agonist could be established to be an atypical antipsychotic drug in phencyclidine and amphetamine models of schizophrenia [30]. These results lead to the hypothesis that A2A receptor agonists can be novel antipsychotic drugs by activating the antagonistic allosteric receptor–receptor interactions in the A2A -D2 heteroreceptor complexes located mainly in the ventral striato-pallidal GABA pathway
The results suggest that the antagonistic allosteric receptor–receptor interactions in
Summary
Cells 2020, 9, 1077 in the plasma membrane, specially extrasynaptic regions [1]. There exist two main receptors for the modulator of adenosine in the brain, namely adenosine A1 and A2A receptors. These results lead to the hypothesis that A2A receptor agonists can be novel antipsychotic drugs by activating the antagonistic allosteric receptor–receptor interactions in the A2A -D2 heteroreceptor complexes located mainly in the ventral striato-pallidal GABA pathway It represents an anti-reward pathway which is overactivated in schizophrenia due to increased activation of its D2 receptors. The salience dysregulation found in schizophrenia is likely produced by pathological increases in the activity of the meso-limbic DA neurons [49] This overactivity can be blocked by restoring the brake on the D2 R protomer signaling by agonist activation of the A2A receptor protomer signaling in several types of A2A -D2 heteroreceptor complexes on the ventral striato-pallidal GABA anti-reward neurons. Multiple adenosine targets were emphasized which involved adenosine A1 and A2A receptor agonists and the enzyme adenosine kinase
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