The functional role of σ receptors in the central nervous system has been investigated extensively. It is now accepted that σ receptors are newly identified receptors which are distinct from opioid and phencyclidine receptors. σ Receptors are proposed to play a role in the antipsychotic, neuroprotective and antiamnesic effects. However, limited evidence suggests involvement of σ receptors in stressful situations related to anxiety or depression. To clarify the functional role of σ receptors in a stressful situation, we have attempted to investigate the effects of various σ receptor ligands on the psychological stress-induced motor suppression, defined as a conditioned fear stress. The conditioned fear stress is attenuated by (+)-SKF-10,047 and dextromethorphan, putative σ receptor agonists, but not by other σ receptor ligand, (+)-pentazocine and 1,3-di(2-tolyl)guanidine. From behavioral studies with an anticonvulsant, phenytoin, we propose that these controversial results may be due to the presence of multiple types of σ receptors, and that the activation of phenytoin-sensitive σ1 receptors may be involved in the ameliorating effects of σ receptors agonists on this stress. Further, our data obtained from neurochemical studies suggests that the dysfunction in the mesolimbic dopaminergic neurons is responsible for the development of conditioned fear stress, and that this stress response is restored through phenytoin-sensitive σ1 receptors, which are closely connected to the dopaminergic neuronal systems. These findings support the hypothesis that phenytoin sensitive σ1 receptors play an important role in the expression of psychological stress-induced motor suppression.
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