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Highlights: [•] D2R-5-HT2A heteroreceptor complexes exist in the ventral and dorsal striatum. [•] LSD and DOI but not TCB2 increased the recognition of the D2R protomer. [•] DOI and LSD but not TCB2 enhanced agonist induced increase of D2R protomer signaling. [•] The increases of D2R protomer function by LSD and DOI involves an allosteric mechanisms. [•] The psychotic actions of LSD and DOI involves biased actions at the 5-HT2AR protomer. [ABSTRACT FROM AUTHOR]

Abstract: The serotonin 5-HT2A receptor (5-HT2AR) and dopamine D2 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 Gq/11 protein and Gi/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. [Copyright &y& Elsevier]

Abstract: Oligomerization of G protein-coupled receptors has become a very important issue in a present molecular pharmacology. In the present study the level of the serotonin 5-HT2A and the dopamine D2 receptor interactions have been studied since it may have a key significance in understanding the mechanism of action of drugs used to treat schizophrenia. With the use of fluorescence resonance energy transfer we demonstrated that the serotonin 5-HT2A receptors form homo- and hetero-dimers with the dopamine D2 receptors and polymorphism H452Y within the 5-HT2A receptor, implicated as a cause of altered response to antipsychotic treatment, disturbs both processes. Clozapine affected the hetero-dimers (5-HT2AH452Y/D2) complexes and increased the otherwise weakened dimerization to the value observed for combination of both wild type receptors, and had no effect on the serotonin receptor homo-dimers (5-HT2AH452Y/5-HT2A), while haloperidol has restored the weakened interaction within homo-complexes and did not effect the hetero-complexes. The obtained data suggest that H452Y polymorphism has an influence not only on the level of constitutive oligomerization of investigated receptors but also it changes their pharmacological properties within both homo- and hetero-complexes. [Copyright &y& Elsevier]

Abstract: In the present study, detailed information is presented on the hetero-dimerization of the serotonin 5-HT2A receptor and the dopamine D2 receptor. Biophysical approaches (fluorescence spectroscopy as well as fluorescence lifetime microscopy) were used to determine the degree of fluorescence resonance energy transfer (FRET) between cyan and yellow fluorescent protein labeled receptor variants co-expressed in human embryonic kidney 293 cells (HEK293). Recorded data demonstrate the existence of energy transfer between the wild-type forms of 5-HT2AR and D2R, pointing toward the formation of hetero-5-HT2AR/D2R dimers and homo-5-HT2AR/5-HT2AR dimers. Moreover, the present study investigates the role of specific motifs (one containing adjacent arginine residues (217RRRRKR222) in the third intracellular loop (ic3) of D2R, and the other consisting of acidic glutamate residues (454EE455) in the C-tail of (5-HT2AR) in the formation of noncovalent complexes between these receptors. Our results suggest that these regions of 5-HT2AR and D2R may be involved in the interaction between these two proteins. On the other hand, the above-mentioned motifs do not play an important role in the homo-dimerization of these receptors. Furthermore, we estimated the influence of specific receptor ligands on the dimerization processes. Agonists (DOI and quinpirole) and antagonists (ketanserin and butaclamol) cause different effects on FRET efficiency depending on whether homo- or hetero-complexes are present. These data may have therapeutic implications, since (using the immunofluorescence double labeling protocols) the co-localization of these two receptors was demonstrated in the medial prefrontal cortex and pars reticulate of the substantia nigra of the rat brain. [ABSTRACT FROM AUTHOR]

Summary. The effects of 3-week treatment with a typical antipsychotic drug chlorpromazine and three atypical antipsychotic drugs (risperidone, olanzapine and perospirone) on the binding to dopamine D2 and serotonin 5-HT2A receptors were examined in the rat stratum and frontal cortex, respectively. Subchronic treatment with chlorpromazine (10 mg/kg) and perospirone (1 mg/kg) significantly increased D2 receptors, while no increase was observed with lower dose of chlorpromazine (5 mg/kg), perospirone (0.1 mg/kg), risperidone (0.25, 0.5 mg/kg) or olanzapine (1, 2 mg/kg). On the other hand, 3-week administration of chlorpromazine (5, 10 mg/kg) and olanzapine (1, 2 mg/kg) significantly decreased 5-HT2A receptors, but risperidone (0.25, 0.5 mg/kg) or perospirone (0.1, 1 mg/kg) had no effect. The measurement of in vivo drug occupation for D2 and 5-HT2A receptors using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) suggested that high occupation of 5-HT2A receptors with lower D2 receptor occupancy might be involved in the absence of up-regulation of D2 receptors after subchronic treatment with some atypical antipsychotic drugs. [ABSTRACT FROM AUTHOR]