In view of the co-distribution of dopamine D2LR and 5-hydroxytryptamine 5-HT2A receptors (D2LR and 5-HT2AR respectively) within inter aim regions of the dorsal and ventral striatum and their role as a target of antipsychotic drugs in this study we assessed the potential existence of D2LR-5-HT2AR heteromers in living cells and the functional consequences of this interaction Thus by means of a proximity-based bioluminescence resonance energy transfer (BRET) approach we demonstrated that the DO and the 5 HT2AR form stable and specific heteromers when expressed in HEK293T mammalian cells Furthermore when the D2LR-5-HT2AR heteromenc signaling was analyzed we found that the 5-HT2AR mediated phospholipase C (PLC) activation was synergistically enhanced by the concomitant activation of the D2LR as shown in a NFAT-luciferase reporter gene assay and a specific and significant rise of the intracellular calcium levels were observed when both receptors were simultaneously activated Conversely when the D2LR-mediated adenylyl cyclase (AC) inhibition was assayed we showed that costimulation of D2LR and 5-HT2AR within the heteromer led to inhibition of the D2LR functioning thus suggesting the existence of a 5-HT2AR-mediated D2LR trans inhibition phenomenon Finally a bioinformatics study reveals that the triplet amino acid homologies LLT (Leu Leu-Thr) and AIS (Ala-Ile-Ser) in TM1 and TM3 respectively of the D2R-5-HT2LR may be Involved in the receptor Interface Overall the presence of the D2LR-5-HT2AR heteromer in discrete brain regions is postulated based on the existence of D2LR-5-HT2A receptor-receptor interactions in living cells and their codistribution inter aim in striatal regions Possible novel therapeutic strategies for treatment of schizophrenia should be explored by targeting this heteromer (C) 2010 Elsevier Inc All rights reserved