Pharmacology
Amisulpride functions primarily as a D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 2.8 nM and 3.2 nM, respectively. Although standard doses in the 400 to 1200 mg a day range used to treat psychosis inhibit dopaminergic neurotransmission, low doses in the 50 to 200 mg range preferentially block inhibitory pre-synaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low dose amisulpride has also been used to treat clinical depression.
Amisulpride and its relative sulpiride have been shown to bind to and activate the GHB receptor at doses that are used for therapeutic purposes. Activation of the GHB receptor is known to inhibit the release of dopamine and even appears to have neuroleptic effects itself. For this reason it is believed that amisulpride and sulpiride's action at this receptor may contribute to their efficacy in treating psychosis..
Though it has long been widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it has recently shown that it also acts as a potent antagonist at the 5-HT7 receptor. Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterize the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice. The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, the mice did not exhibit an antidepressant response upon treatment with amisulpride. These results indicate that 5-HT7 receptor antagonism plays a major role in the antidepressant effects of amisulpride.
