Sigma-receptor ligands and anti-stress actions

The functional role of sigma receptors in the central nervous system has been investigated extensively. Sigma₁-receptors have been shown to play an important role in antidepressive effects since selective sigma₁-receptor agonists, as well as typical antidepressants, reduced the immobility time in the forced swimming and tail suspension tests. The reduction of immobility by sigma₁-receptor agonists is antagonized by NE-100, a sigma₁-receptor antagonist. It has been suggested that sigma receptors are involved in anxiety since Lu 28-179, a sigma₂-receptor agonist, has anxiolytic properties in rodents. In addition to the depressive animal model, phenytoin- sensitive sigma₁-receptor agonists such as (+)-SKF-10,047 and dextromethorphan attenuate the conditioned fear stress (CFS) response (which is not influenced by typical anxiolytics and antidepressants) in rodents, the attenuating effects being mediated through phenytoinsensitive sigma₁receptors, which are closely connected to the mesolimbic dopaminergic systems. Furthermore, neurosteroids such as dehydroepiandrosterone sulfate also attenuate the CFS response, the effect being mediated via sigma₁ receptors. These findings suggest that sigma receptors are involved in stress-induced pathophysiological changes such as depression and anxiety and that phenytoin-sensitive sigma₁-receptor ligands are useful for the treatment of affective disorders, particularly those considered to be treatment-resistant.