Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-ol-20-one

Wieland, Scott; Lan, Nancy C.; Mirasedeghi, Seid; Gee, Kelvin W.

doi:10.1016/0006-8993(91)91658-n

Cited by 283 publications

(104 citation statements)

References 24 publications

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“…Thus, in vivo administration of allopregnanolone has a marked anticon¯ict e ect and antagonizes the action of stress on the release of various neurotransmitters in freely moving rats (Crawley et al, 1986;Bitran et al, 1991;Wieland et al, 1991;Dazzi et al, 1996;Motzo et al, 1996). The marked increase in the brain content of these two neuroactive steroids induced by CB compounds might therefore be expected to reduce the e ects of stress on neuronal excitability and associated behaviour.…”

Section: Discussionmentioning

confidence: 99%

“…Depending on their concentration, the binding of such neuroactive steroids to GABA A receptors results in either potentiation of GABA-induced Cl 7 currents or a direct opening of the receptor-operated Cl 7 channel Harrison et al, 1987;Puia et al, 1990;Hill-Venning et al, 1994;Lambert et al, 1995), which may account for their anxiolytic, anticonvulsant, hypnotic and anaesthetic e ects (Holzbauer et al, 1985;Crawley et al, 1986;Mendelson et al, 1987;Belelli et al, 1990;Bitran et al, 1991;Wieland et al, 1991;Kokate et al, 1994;Lambert et al, 1995;Concas et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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2‐Phenyl‐imidazo[1,2‐a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats

Serra

Madau

Chessa

et al. 1999

British J Pharmacology

105

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3 Intraperitoneal administration of CB compounds (3 ± 50 mg kg 71 ) induced a dose-dependent increase in the concentrations of neuroactive steroids in plasma and brain. The brain concentrations of pregnenolone, progesterone, allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) showed maximal increases in 96+3, 126+14, 110+12 and 70+13% above control, respectively, 30 to 60 min after injection of CB 34 (25 mg kg 71 ). CB 34 also increased the brain concentrations of neuroactive steroids in adrenalectomized-orchiectomized rats, although to a lesser extent than in sham-operated animals, suggesting that CB compounds stimulate brain steroidogenesis independently of their e ects on peripheral tissues. 4 The increase in brain and plasma neurosteroid content induced by CB 34 was associated with a marked anticon¯ict e ect in the Vogel test. Our results indicate that the three CB compounds tested are speci®c and potent agonists at peripheral benzodiazepine receptors, and that they stimulate steroidogenesis in both the brain and periphery.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

2‐Phenyl‐imidazo[1,2‐a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats

Serra

Madau

Chessa

et al. 1999

British J Pharmacology

105

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“…It is a positive allosteric modulator of g-aminobutyric acid type A (GABA A ) receptors, potentiating GABAergic neurotransmission in a manner that is 20-fold more potent than benzodiazepines and 200-fold more potent than barbiturates Morrow et al, 1987Morrow et al, , 1990. Allopregnanolone demonstrates marked anxiolytic (Crawley et al, 1986;Wieland et al, 1991) and anticonvulsant activity (Kokate et al, 1994(Kokate et al, , 1996Devaud et al, 1995), likely secondary to GABA A receptor potentiation. Recent evidence also suggests that allopregnanolone may be relevant to antipsychotic drug action and schizophrenia pathophysiology (Marx et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

Marx

VanDoren

Duncan

et al. 2003

Neuropsychopharmacol

133

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The neuroactive steroid allopregnanolone is a potent g-aminobutyric acid type A (GABA A ) receptor modulator with anxiolytic and anticonvulsant effects. Olanzapine and clozapine also have anxiolytic-like effects in behavioral models. We therefore postulated that olanzapine and clozapine would elevate allopregnanolone levels, but risperidone and haloperidol would have minimal effects. Male rats received intraperitoneal olanzapine (2.5-10.0 mg/kg), clozapine (5.0-20.0 mg/kg), risperidone (0.1-1.0 mg/kg), haloperidol (0.1-1.0 mg/ kg), or vehicle. Cerebral cortical allopregnanolone and peripheral progesterone and corticosterone levels were determined. Adrenalectomized animals were also examined. Both olanzapine and clozapine increased cerebral cortical allopregnanolone levels, but neither risperidone nor haloperidol had significant effects. Olanzapine and clozapine also increased serum progesterone and corticosterone levels. Adrenalectomy prevented olanzapine-and clozapine-induced elevations in allopregnanolone. Allopregnanolone induction may contribute to olanzapine and clozapine anxiolytic, antidepressant, and mood-stabilizing actions. Alterations in this neuroactive steroid may result in the modulation of GABAergic and dopaminergic neurotransmission, potentially contributing to antipsychotic efficacy.

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“…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.…”

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confidence: 99%

Neurosteroids Ameliorate Conditioned Fear Stress An Association with Sigma1 Receptors

Noda

Kamei

et al. 2000

Neuropsychopharmacology

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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; 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...

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Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-ol-20-one

Cited by 283 publications

References 24 publications

2‐Phenyl‐imidazo[1,2‐a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats

2‐Phenyl‐imidazo[1,2‐a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

Neurosteroids Ameliorate Conditioned Fear Stress An Association with Sigma1 Receptors

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