Evidence that 5α-pregnan-3α-ol-20-one is the metabolite responsible for progesterone anesthesia

Mok, Wai Man; Krieger, Neil R.

doi:10.1016/0006-8993(90)91792-f

Cited by 45 publications

(20 citation statements)

References 19 publications

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“…Other studies have not demonstrated a beneficial effect of progestins for cognitive performance (Freeman et al, 1993;Zou et al, 2000); however, these effects may be due to 3α,5α-THP's dose-dependent effects for behavior in this task. Notably, higher dosages of 3α,5α-THP can have anxiolytic or sedative effects (Bitran et al, 1991;1999;Korneyev & Costa, 1996;Mok & Krieger, 1990;Seyle, 1941), which would interfere with consolidation and performance. However, we have shown that the dosages used in the present study produce physiological progestin levels in the hippocampus (Walf et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task

Frye

Duffy

Walf

2007

Neurobiology of Learning and Memory

218

219

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Steroid modulation of cognitive function has focused on estrogen (E 2 ), but progestins naturally covary with E 2 and may also influence cognitive performance. Spatial performance in the object placement task over endogenous hormonal states in which E 2 and progestins vary, and when E 2 and/ or progestins were administered, was examined. Experiment 1: Rats in proestrus or estrus had significantly better performance in the object placement task than did diestrous rats. Experiment 2: Rats in the third trimester, post-partum, or lactation exhibited significantly better performance in the object placement task than did rats in the first trimester. Experiment 3: Ovariectomized (ovx) rats administered 17β-estradiol (0.9 mg/kg, subcutaneously (sc), progesterone (P; 4 mg/kg, sc), or E 2 and P, immediately after training in the object placement task, performed significantly better when tested 4 hours later, than did control rats administered vehicle (sesame oil 0.2 cc). Experiment 4: Ovx rats administered E 2 or P with a one and a half hour delay after training in the object placement task, did not perform differently than vehicle-administered controls. Experiment 5: Ovx rats administered post-training E 2 , which has a high affinity for both E 2 receptor (ER)α and β isoforms, or propyl pyrazole triol (PPT; 0.9 mg/kg, sc), which is more selective for ERα than ERβ, had significantly better performance in the object placement task than did rats administered vehicle or diarylpropionitrile (DPN; 0.9 mg/kg, sc), an ERβ selective ligand. Experiment 6: Ovx rats administered P, or its metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP; 4 mg/kg, sc), immediately post-training performed significantly better in the object placement task than did vehicle control rats. Thus, performance in the object placement task is better when E 2 and/or P are naturally elevated or when E 2 , the ERα selective ER modulator PPT, P, or its metabolite, 3α,5α-THP, are administered post-training.

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Section: Discussionmentioning

confidence: 99%

Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task

Frye

Duffy

Walf

2007

Neurobiology of Learning and Memory

218

219

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“…3a-OH-5a-pregnan-20-one (allopregnanolone) and 3a-OH-5b-pregnan-20-one (pregnanolone), have barbiturate-and benzodiazepine-like effects mediated through their binding to the gamma aminobutyric acid (GABA A ) receptor complex in the brain, thereby eliciting hypnotic, anxiolytic, and anti-epileptic effects (7,8). In humans, progesterone can, in large doses, induce anesthesia, and this effect is mediated via the metabolism of progesterone to allopregnanolone and pregnanolone (8,9). Similarly, the acute anxiolytic effect of progesterone in laboratory animals is mediated through its conversion to allopregnanolone, active on the GABA A receptor (10).…”

Section: Introductionmentioning

confidence: 99%

Progesterone effects during sequential hormone replacement therapy

Andréen

Bixo

Nyberg

et al. 2003

European Journal of Endocrinology

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Objective: The aim was to investigate the effect on mood and the physical symptoms of two dosages of natural progesterone and a placebo in postmenopausal women with and without a history of premenstrual syndrome (PMS). Design: A randomized, placebo-controlled, double-blind, crossover study was performed. Method: Postmenopausal women ðn ¼ 36Þ with climacteric symptoms were recruited. They received 2 mg estradiol continuously during three 28-day cycles. Vaginal progesterone suppositories with 800 mg/day, 400 mg/day, or placebo were added sequentially for 14 days per cycle. Daily symptom ratings using a validated rating scale were kept. Results: Women without a history of PMS showed cyclicity in both negative mood and physical symptoms while on 400 mg/day progesterone but not on the higher dose or the placebo. Women without a history of PMS had more physical symptoms on progesterone treatment compared with placebo. Women with prior PMS reported no progesterone-induced symptom cyclicity. Conclusion: In women without prior PMS natural progesterone caused negative mood effects similar to those induced by synthetic progestogens.

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“…The PR is composed of two protein isoforms, PR-A and PR-B subtypes that are expressed from the same PR gene. In addition, current experimental evidence indicates that progesterone influences neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABA A receptors (13)(14)(15)(16). However, the extent to which the sedative-hypnotic action of progesterone and allopregnanolone requires PRs is unclear.…”

Section: Introductionmentioning

confidence: 99%

Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes

Reddy¹,

Zeng²

2007

Methods and Findings in Experimental and Clinical Pharmacology

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SUMMARY-Progesterone affects the function of the brain by multiple mechanisms. The physiological effects of progesterone are mediated by interaction of the hormone with progesterone receptors (PRs), which are widely expressed in the hypothalamus, hippocampus and limbic areas. The PR is composed of two protein isoforms, PR-A and PR-B, which are expressed from a single PR gene. In addition, progesterone influences neuronal activity through its conversion to allopregnanolone, a neurosteroid that acts as a positive allosteric modulator of GABA A receptors. However, the role of PRs in the sedative-hypnotic action of neurosteroids is unclear. In this study, PR knockout (PRKO) mice were used as model to study the sedative-anesthetic actions of the progesterone-derived neurosteroid allopregnanolone and the non-competitive NMDA receptor antagonist ketamine. Mice were confirmed to be PR deficient by genotyping and immunohistochemistry of PR expression in the brain. Anesthetic potency was evaluated by the loss of the righting reflex paradigm. Allopregnanolone induced anesthetic activity was similar in PRKO mice and their wild-type littermates, suggesting that PRs are not involved in the anesthetic response to allopregnanolone. However, the non-competitive NMDA receptor antagonist ketamine has significantly reduced anesthetic potency in PRKO mice, suggesting a possible developmental plasticity of glutamate receptors. There was no marked gender-related difference to ketamine response in both genotypes. In conclusion, these results suggest that the neurosteroid allopregnanolone and ketamine produce differential anesthetic response in mice lacking PRs.

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Evidence that 5α-pregnan-3α-ol-20-one is the metabolite responsible for progesterone anesthesia

Cited by 45 publications

References 19 publications

Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task

Estrogens and progestins enhance spatial learning of intact and ovariectomized rats in the object placement task

Progesterone effects during sequential hormone replacement therapy

Differential anesthetic activity of ketamine and the GABAergic neurosteroid allopregnanolone in mice lacking progesterone receptor A and B subtypes

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