Effects of sigma receptor ligands on conditioned fear stress.

Mice or rats exhibit a marked suppression of motility when they are replaced in the same environment in which they previously received an electric footshock. To clarify the functional role of sigma receptors in a stressful situation, we investigated the behavioral and neurochemical effects of various sigma receptor ligands on this psychological stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 and dextromethorphan, putative sigma receptor agonists, reversed the conditioned fear stress. However, other sigma receptor ligands, (+)-pentazocine and 1,3-di(2-tolyl)guanidine had no effect. Further, (+)-SKF-10,047, but not (+)-pentazocine, restored the decreased dopamine turnover in the nucleus accumbens in the stressed group to the control level, the effect being consistent with its behavioral effect. We indicated that these controversial results may be due to the presence of multiple types of sigma receptors, and that the activation of phenytoin-sensitive sigma 1 receptors may be involved in the ameliorating effects of sigma receptor agonists on this stress. Our findings suggest 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 sigma 1 receptors, which are closely connected to the dopaminergic neuronal systems.