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Psychopharmacology

, Volume 205, Issue 1, pp 119–128 | Cite as

Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo

  • Atheir I. Abbas
  • Peter B. Hedlund
  • Xi-Ping Huang
  • Thuy B. Tran
  • Herbert Y. Meltzer
  • Bryan L. Roth
Original Investigation

Abstract

Rationale

Amisulpride is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia, a mild form of depression, in Italy. Amisulpride has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials. In part because of the selective D2/D3 receptor antagonist properties of amisulpride, it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties.

Objectives

The purpose of these studies was to determine if amisulpride’s antidepressant actions are mediated by off-target interactions with other receptors.

Materials and Methods

We performed experiments that: (1) examined the pharmacological profile of amisulpride at a large number of central nervous system (CNS) molecular targets and, (2) after finding high potency antagonist affinity for human 5-HT7a serotonin receptors, characterized the actions of amisulpride as an antidepressant in wild-type and 5-HT7 receptor knockout mice.

Results

We discovered that amisulpride was a potent competitive antagonist at 5-HT7a receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo. Significantly, and in contrast to their wild-type littermates, 5-HT7 receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression, the tail suspension test and the forced swim test.

Conclusions

These results indicate that 5-HT7a receptor antagonism, and not D2/D3 receptor antagonism, likely underlies the antidepressant actions of amisulpride.

Keywords

Amisulpride 5-HT7 5-HT7 antagonist Antidepressant Atypical antipsychotic DAN 2163 

Notes

Acknowledgments

A.A., X.P.H., T.B.T., and B.L.R. were supported by NIMH61887, U19MH82441, and the NIMH Psychoactive Drug Screening Program; B.L.R. received additional support as a NARSAD Distinguished Investigator. A.A. was also supported by the CWRU MSTP and NIH T32 GM007250. P.B.H. was supported by NIMH MH73923.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Atheir I. Abbas
    • 1
  • Peter B. Hedlund
    • 2
  • Xi-Ping Huang
    • 3
  • Thuy B. Tran
    • 3
  • Herbert Y. Meltzer
    • 4
  • Bryan L. Roth
    • 3
    • 5
    • 6
    • 7
  1. 1.Department of Biochemistry, School of MedicineCase Western Reserve UniversityClevelandUSA
  2. 2.Department of Molecular BiologyThe Scripps Research InstituteLa JollaUSA
  3. 3.National Institute of Mental Health Psychoactive Drug Screening Program, Department of Pharmacology, School of MedicineUniversity of North CarolinaChapel HillUSA
  4. 4.Department of Psychiatry, School of MedicineVanderbilt UniversityNashvilleUSA
  5. 5.Department of Pharmacology and Psychiatry, School of MedicineUniversity of North CarolinaChapel HillUSA
  6. 6.Lineberger Cancer Center, School of MedicineUniversity of North CarolinaChapel HillUSA
  7. 7.Department of Medicinal Chemistry, School of PharmacyUniversity of North CarolinaChapel HillUSA

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