Potential antidepressant activity of sigma ligands

Despite many years' studies of antidepressant drugs (ADs), their mechanism of action still remains unclear. Recently, it has been postulated that substances capable of reducing neurotransmission at the NMDA complex may represent a new class of ADs. Since several ADs have a high affinity for sigma receptors, the sigma binding site may be a relevant mechanism in antidepressant action. Moreover, sigma ligands are able to modulate the activity of the central neurotransmitter systems, including noradrenergic, serotonergic, dopaminergic and glutamatergic (NMDA) ones, which are seemingly important for the mechanism of action of known ADs. The existence of at least two different subtypes of sigma receptors, denoted sigma1 and sigma2 is now widely accepted. The selective agonists of both sigma receptor subtypes are available at present. In particular, a potential antidepressant activity of sigma1 receptor agonists has been postulated, since the antidepressive-like actions of these compounds have been shown in animal models. This article reviews the findings related to potential antidepressant activity of new, selective sigma ligands.