Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor
Neurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulate...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2014-04-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00106/full |
| _version_ | 1828475905418199040 |
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| author | Cheryl A Frye Carolyn J Koonce Alicia A Walf |
| author_facet | Cheryl A Frye Carolyn J Koonce Alicia A Walf |
| author_sort | Cheryl A Frye |
| collection | DOAJ |
| description | Neurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulated and the novel (i.e. non steroid receptor) targets for steroid action for behavior. One endpoint of interest has been lordosis, the mating posture of female rodents. Allopregnanolone is necessary and sufficient for lordosis, and the brain circuitry underlying it, such as actions in the midbrain ventral tegmental area (VTA), has been well-characterized. Published and recent findings supporting a dynamic role of allopregnanolone are included in this review. First, contributions of ovarian and adrenal sources of precursors of allopregnanolone, and the requisite enzymatic actions for de novo production in the central nervous system will be discussed. Second, how allopregnanolone produced in the brain has actions on behavioral processes that are independent of binding to steroid receptors, but instead involve rapid modulatory actions via neurotransmitter targets (e.g. -amino butyric acid-GABA, n-methyl-D-aspartate- NMDA) will be reviewed. Third, a recent focus on characterizing the role of a promiscuous nuclear receptor, pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism and expressed in the VTA, as a target for allopregnanolone and how this relates to both actions and production of allopregnanolone will be addressed. For example, allopregnanolone can bind PXR and knocking down expression of PXR in the midbrain VTA attenuates actions of allopregnanolone via NMDA and/or GABAA for lordosis. Our understanding of allopregnanolone’s actions in the VTA for lordosis has been extended to reveal the role of allopregnanolone for broader, clinically-relevant questions, such as neuropsychiatric disorders, epilepsy, and aging. |
| first_indexed | 2024-12-11T06:20:51Z |
| format | Article |
| id | doaj.art-01fbf014858f4742b124b1532b570d7c |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-11T06:20:51Z |
| publishDate | 2014-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-01fbf014858f4742b124b1532b570d7c2022-12-22T01:17:50ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022014-04-01810.3389/fncel.2014.0010686450Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptorCheryl A Frye0Carolyn J Koonce1Alicia A Walf2University of Alaska- FairbanksUniv of Alaska- FairbanksUniv of Alaska- FairbanksNeurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulated and the novel (i.e. non steroid receptor) targets for steroid action for behavior. One endpoint of interest has been lordosis, the mating posture of female rodents. Allopregnanolone is necessary and sufficient for lordosis, and the brain circuitry underlying it, such as actions in the midbrain ventral tegmental area (VTA), has been well-characterized. Published and recent findings supporting a dynamic role of allopregnanolone are included in this review. First, contributions of ovarian and adrenal sources of precursors of allopregnanolone, and the requisite enzymatic actions for de novo production in the central nervous system will be discussed. Second, how allopregnanolone produced in the brain has actions on behavioral processes that are independent of binding to steroid receptors, but instead involve rapid modulatory actions via neurotransmitter targets (e.g. -amino butyric acid-GABA, n-methyl-D-aspartate- NMDA) will be reviewed. Third, a recent focus on characterizing the role of a promiscuous nuclear receptor, pregnane xenobiotic receptor (PXR), involved in cholesterol metabolism and expressed in the VTA, as a target for allopregnanolone and how this relates to both actions and production of allopregnanolone will be addressed. For example, allopregnanolone can bind PXR and knocking down expression of PXR in the midbrain VTA attenuates actions of allopregnanolone via NMDA and/or GABAA for lordosis. Our understanding of allopregnanolone’s actions in the VTA for lordosis has been extended to reveal the role of allopregnanolone for broader, clinically-relevant questions, such as neuropsychiatric disorders, epilepsy, and aging.http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00106/fullReproductionVentral Tegmental AreaneurosteroidmidbrainAllopregnanolonenon-genomic |
| spellingShingle | Cheryl A Frye Carolyn J Koonce Alicia A Walf Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor Frontiers in Cellular Neuroscience Reproduction Ventral Tegmental Area neurosteroid midbrain Allopregnanolone non-genomic |
| title | Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor |
| title_full | Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor |
| title_fullStr | Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor |
| title_full_unstemmed | Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor |
| title_short | Novel receptor targets for production and action of allopregnanolone in the central nervous system: a focus on pregnane xenobiotic receptor |
| title_sort | novel receptor targets for production and action of allopregnanolone in the central nervous system a focus on pregnane xenobiotic receptor |
| topic | Reproduction Ventral Tegmental Area neurosteroid midbrain Allopregnanolone non-genomic |
| url | http://journal.frontiersin.org/Journal/10.3389/fncel.2014.00106/full |
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