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


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


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.
Abbas
Atheir I
AI
Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Hedlund
Peter B
PB
Huang
Xi-Ping
XP
Tran
Thuy B
TB
Meltzer
Herbert Y
HY
Roth
Bryan L
BL