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.
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