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

Research output: Contribution to journalArticlepeer-review

206 Scopus citations

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-HT 7a 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.

Original languageEnglish (US)
Pages (from-to)119-128
Number of pages10
JournalPsychopharmacology
Volume205
Issue number1
DOIs
StatePublished - Jul 2009

Keywords

  • 5-HT
  • 5-HT antagonist
  • Amisulpride
  • Antidepressant
  • Atypical antipsychotic
  • DAN 2163

ASJC Scopus subject areas

  • Pharmacology

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