Abstract
The serotonin 5-HT 2A receptor (5-HT 2AR) and dopamine D 2 receptor (D 2R) are high-affinity G protein-coupled receptor targets for two different classes of antipsychotic drugs used to treat schizophrenia. Interestingly, the antipsychotic effects are not based on the regulation of same signaling mediators since activation of the 5-HT 2AR and of the D 2R regulate G q/11 protein and G i/o protein, respectively. Here we use radioligand binding and second messenger production assays to provide evidence for a functional crosstalk between 5-HT 2AR and D 2R in brain and in HEK293 cells. D 2R activation increases the hallucinogenic agonist affinity for 5-HT 2AR and decreases the 5-HT 2AR induced inositol phosphate production. In vivo, 5-HT 2AR expression is necessary for the full effects of D 2R antagonist on MK-801-induced locomotor activity. Co-immunoprecipitation studies show that the two receptors can physically interact in HEK293 cells and raise the possibility that a receptor heterocomplex mediates the crosstalk observed. The existence of this 5-HT 2AR-D 2R heteromer and crosstalk may have implications for diseases involving alterations of serotonin and dopamine systems and for the development of new classes of therapeutic drugs.
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