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Original Article |
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Neuropsychopharmacology (2000) 23 276-284.10.1038/sj.npp.1395511
Neurosteroids Ameliorate Conditioned Fear Stress: An Association with Sigma1 Receptors
Yukihiro Noda1 Ph.D, Hiroyuki Kamei1 Ph.D, Yukie Kamei1,2 MS, Taku Nagai1,2 MS, Mikio Nishida2 Ph.D and Toshitaka Nabeshima1,2 Ph.D |
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1Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan
2Department of Clinical Pharmacy, Faculty of Pharmacy, Meijo University, Nagoya, Japan
Correspondence: Dr Toshitaka Nabeshima, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan
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ABSTRACT
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Mice exhibited a marked suppression of motility (conditioned fear stress) when placed in an environment in which they had previously received an electric footshock. This conditioned fear stress response was dose-dependently attenuated by neurosteroids such as dehydroepiandrosterone sulfate (DHEAS; 25 and 50 mg/kg, s.c.) and pregnenolone sulfate (PREGS; 10-50 mg/kg, s.c.), and by a putative sigma1 receptor agonist, (+)-N-allylnormetazocine ((+)-SKF-10,047; 3 and 6 mg/kg, s.c.). However, progesterone (PROG; 10-50 mg/kg, s.c.) and allopregnanolone (5 and 20 mg/kg, s.c.) had no effect on this stress response. The attenuating effects of DHEAS (50 mg/kg, s.c.), PREGS (50 mg/kg, s.c.), and (+)-SKF-10,047 (6 mg/kg, s.c.) were reversed by NE-100 (5 mg/kg, i.p.), a sigma1 receptor antagonist and PROG (5 or 10 mg/kg, i.p.). When DHEAS (25 mg/kg) was co-administered with (+)-SKF-10,047 (3 mg/kg) at doses that do not affect the conditioned fear stress response by themselves, motor suppression was significantly attenuated. In mice showing the conditioned fear stress response, the serum concentration of DHEAS was lower than that in non-shocked mice. These results suggest that the attenuating effects of DHEAS and PREGS on the conditioned fear stress response are mediated via sigma1 receptors and that PROG has a sigma1 receptor antagonistic property. Further, the endogenous DHEAS may be involved in the expression of conditioned fear stress response in mice.
Keywords: Neurosteroids; Sigma1 receptors; Conditioned fear stress; DHEAS |
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