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

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Abbas AI, Hedlund PB, Huang XP, Tran TB, Meltzer HY, Roth BL

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

Psychopharmacology (Berl). 2009 Jul;205(1):119-28. doi: 10.1007/s00213-009-1521-8. Epub 2009 Apr 1.

PubMed ID

19337725 [ View in PubMed

]

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 D(2)/D(3) 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-HT(7) receptor knockout mice. RESULTS: We discovered that amisulpride was a potent competitive antagonist at 5-HT(7a) 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-HT(7) 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-HT(7a) receptor antagonism, and not D(2)/D(3) receptor antagonism, likely underlies the antidepressant actions of amisulpride.

DrugBank Data that Cites this Article

Drugs

Amisulpride

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Amisulpride	5-hydroxytryptamine receptor 7	Protein	Humans	Yes	Antagonist	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Amisulpride	5-hydroxytryptamine receptor 2A	Ki (nM)	8304	N/A	N/A	Details