Neurosteroids Ameliorate Conditioned Fear Stress An Association with Sigma1 Receptors

Abstract

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; s.c.), and by a putative sigma 1 047; 3 and 6 mg/kg, s.c.). However, progesterone (PROG; 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 ( ϩ )- 047 (6 mg/kg, s.c.) were reversed by i.p.), a sigma 1 receptor antagonist and PROG (5 or 10 mg/kg, i.p.). When DHEAS (25 mg/kg) was co-administered with ( ϩ )- 047 (3 mg/kg) Neurosteroids are synthesized in the brain, either de novo from cholesterol or from steroid hormone precursors, and accumulate in the nervous system to levels that are at least in part independent of steroidogenic gland secretion (Baulieu 1981). Neurosteroids, such as progesterone (PROG), pregnenolone (PREG), dehydroepiandrosterone (DHEA), and their respective sulfate ester (PREGS or DHEAS), are involved in regulating the imbalance between excitation and inhibition in the CNS (Wu et al. 1991). The neurosteroids, allopregnanolone, allotetrahydrodeoxycorticosterone, PREGS, and DHEAS have been shown to possess antistress, anxiolytic, and antiamnesic properties in experimental animal models (Bitran et al. 1991;Brot et al. 1997;Maurice et al. , 1999Urani et al. 1998;Wieland et al. 1991). Recent evidence suggests that DHEAS and PREGS also play an important role in depression. Interestingly, decreased levels of DHEA, DHEAS, and PREGS have been associated with depression, cognitive dysfunction, aging, and other neurological conditions (Orentreich et al. 1984;Vallée et al. 1997), and DHEA improves the depression score in patients (Wolkowitz et al. 1997). However, the From the Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine (YN, HK, YK, TN, TN), Nagoya, Japan; and Department of Clinical Pharmacy, Faculty of Pharmacy, Meijo University (YK, TN, MN), Nagoya, Japan. receptor agonist, ( ϩ )-N-allylnormetazocine (( ϩ )-Address correspondence to: Dr. Toshitaka Nabeshima, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.Received October 18, 1999; revised February 2, 2000; accepted February 18, 2000. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 23 , NO . 3 Neurosteroids and Sigma 1 Receptors 277 mechanism underlying the beneficial effects of neurosteroids is not yet known.Neurosteroids have been shown to affect the activity of neurotransmitter systems, which are involved in a variety of neuropsychiatric illnesses. DHEAS and PREGS are negative allosteric modulators of the ␥ -aminobutyric acid (GABA) A receptors (Majewska 1992), and positive modulators of N-methyl-D-aspartate (NMDA) receptor-mediated res...

Progesterone Attenuates Corticotropin-Releasing Factor-Enhanced But Not Fear-Potentiated Startle via the Activity of Its Neuroactive Metabolite, Allopregnanolone

“…Because the BNST is implicated in emotional reactivity more akin to anxiety than stimulus-specific fear , the current results suggest that P may be affecting brain systems involved in anxiety versus stimulus-specific fear. In agreement with this, a recent study reported that neither THP nor P reduced the suppression of motility after the onset of conditioned fear stimulus (Noda et al, 2000).…”

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

“…376 In addition, PREGS can attenuate the conditioned fear stress response via ó 1 receptors. 377 Albeit speculative, these findings suggest that PREG and PREGS may have therapeutic potential for improving cognitive deficit observed in schizophrenia.…”

The antidepressant-like effect induced by the sigma1 (σ1) receptor agonist igmesine involves modulation of intracellular calcium mobilization

“…The neuroactive steroid/s 1 receptor interaction was first demonstrated using binding studies (Su et al 1988;Yamada et al 1994;Maurice et al 1996a), then reported in physiological (Monnet et al 1995;Debonnel et al 1996) and behavioral studies (Maurice et al 1997Reddy et al 1998;Urani et al 1998;Noda et al 2000). In particular, progesterone acts as a potent s 1 receptor antagonist, and physiological variations in the central levels of the steroid directly affect the behavioral efficacy of s 1 receptor agonists Urani et al 2001).…”