Journal
NEUROPHARMACOLOGY
Volume 61, Issue 4, Pages 770-777Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2011.05.023
Keywords
Serotonin 5-HT2A receptor; Dopamine D-2 receptor; Crosstalk; Schizophrenia; Hallucinogen; Antipsychotic
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Funding
- NIH [PO1 DA012923, R01 MH084894]
- NARSAD
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The serotonin 5-HT2A receptor (5-HT2AR) and dopamine D-2 receptor (D2R) 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-HT2AR and of the D2R 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-HT2AR and D2R in brain and in HEK293 cells. D2R activation increases the hallucinogenic agonist affinity for 5-HT2AR and decreases the 5-HT2AR induced inositol phosphate production. In vivo, 5-HT2AR expression is necessary for the full effects of D2R 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-HT2AR-D2R 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. (C) 2011 Published by Elsevier Ltd.
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