Effects of σ 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 σ receptors in a stressful situation, we investigated the behavioral and neurochemical effects of various σ receptor ligands on this psychological stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 and dextromethorphan, putative σ receptor agonists, reversed the conditioned fear stress. However, other σ 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 σ receptors, and that the activation of phenytoin-sensitive σ₁ receptors may be involved in the ameliorating effects of σ 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 σ₁ receptors, which are closely connected to the dopaminergic neuronal systems.