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

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. The purpose of these studies was to determine if amisulpride’s antidepressant actions are mediated by off-target interactions with other receptors. 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. 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-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. These results indicate that 5-HT_7a receptor antagonism, and not D₂/D₃ receptor antagonism, likely underlies the antidepressant actions of amisulpride. [ABSTRACT FROM AUTHOR]