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
phenytoin-sensitive sigma1 receptors, 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.