Role of (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors in amelioration of conditioned fear stress in rats: association with mesolimbic dopaminergic systems

Rats exhibited a marked suppression of motility when they were re-placed in the same environment as that in which they had previously received an electric footshock. We examined the behavioral and neurochemical effects of (+)-N-allylnormetazocine hydrochloride ((+)-SKF-10,047) and (+)-pentazocine, putative sigma 1 receptor ligands, on this psychological-stress-induced motor suppression, defined as a conditioned fear stress. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently attenuated the conditioned fear stress, whereas (+)-pentazocine failed to do so even at a higher dose (32 mg/kg). In rats showing the conditioned fear stress, dopamine turnover (i.e., the ratio of dopamine metabolites/dopamine contents) was decreased in the nucleus accumbens and was increased in the medial prefrontal cortex, but remained unchanged in the striatum. (+)-SKF-10,047 (3 and 6 mg/kg) dose-dependently reversed the decreased dopamine turnover in the nucleus accumbens without changing the increased dopamine turnover in the medial prefrontal cortex. (+)-Pentazocine (32 mg/kg) did not affect the stress-induced changes in dopamine turnover in these brain regions. Thus, the decreased dopamine turnover in the nucleus accumbens appears to be involved in the conditioned fear stress. These results suggest that (+)-SKF-10,047 ameliorates the conditioned fear stress by reversing the psychological stress-induced dysfunction in the mesolimbic dopaminergic systems, and that the (+)-SKF-10,047-sensitive sub-population of sigma 1 receptors may play in important role in this stress response.