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Differential profile of typical, atypical and third generation antipsychotics at human 5-HT7a receptors coupled to adenylyl cyclase: detection of agonist and inverse agonist properties

  • Isabelle Rauly-Lestienne
  • Elisa Boutet-Robinet
  • Marie-Christine Ailhaud
  • Adrian Newman-Tancredi
  • Didier CussacEmail author
Original Article

Abstract

5-HT7 receptors are present in thalamus and limbic structures, and a possible role of these receptors in the pathology of schizophrenia has been evoked. In this study, we examined binding affinity and agonist/antagonist/inverse agonist properties at these receptors of a large series of antipsychotics, i.e., typical, atypical, and third generation compounds preferentially targeting D2 and 5-HT1A sites. Adenylyl cyclase (AC) activity was measured in HEK293 cells stably expressing the human (h) 5-HT7a receptor isoform. 5-HT and 5-CT increased cyclic adenosine monophosphate level by about 20-fold whereas (+)-8-OH-DPAT, the antidyskinetic agent sarizotan, and the novel antipsychotic compound bifeprunox exhibited partial agonist properties at h5-HT7a receptors stimulating AC. Other compounds antagonized 5-HT-induced AC activity with pK B values which correlated with their pK i as determined by competition binding vs [3H]5-CT. The selective 5-HT7 receptor ligand, SB269970, was the most potent antagonist. For antipsychotic compounds, the following rank order of antagonism potency (pK B) was ziprasidone > tiospirone > SSR181507 ≥ clozapine ≥ olanzapine > SLV-314 > SLV-313 ≥ aripiprazole ≥ chlorpromazine > nemonapride > haloperidol. Interestingly, pretreatment of HEK293-h5-HT7a cells with forskolin enhanced basal AC activity and revealed inverse agonist properties for both typical and atypical antipsychotics as well as for aripiprazole. In contrast, other novel antipsychotics exhibited diverse 5-HT7a properties; SLV-313 and SLV-314 behaved as quasi-neutral antagonists, SSR181507 acted as an inverse agonist, and bifeprunox as a partial agonist, as mentioned above. In conclusion, the differential properties of third generation antipsychotics at 5-HT7 receptors may influence their antipsychotic profile.

Keywords

5-HT7 receptor Antipsychotics Adenylyl cyclase Inverse agonists Clozapine Aripiprazole Bifeprunox 

Notes

Acknowledgments

We sincerely thank Claudie Cathala for the construction of plasmid vectors, Liesbeth Bruins Slot and Peter Heusler for expert helpful advice on the manuscript.

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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Isabelle Rauly-Lestienne
    • 1
  • Elisa Boutet-Robinet
    • 1
  • Marie-Christine Ailhaud
    • 1
  • Adrian Newman-Tancredi
    • 2
  • Didier Cussac
    • 1
    Email author
  1. 1.Department of Cellular and Molecular BiologyCentre de Recherche Pierre FabreCastres CedexFrance
  2. 2.Division of Neurobiology 2Centre de Recherche Pierre FabreCastres CedexFrance

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