Biology:Neurosteroid

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Short description: Compounds that affect neuronal excitability through modulation of specific ionotropic receptors
Zuranolone, an example of a neurosteroid, used for the treatment of postpartum depression

Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors.[1][2] The term neurosteroid was coined by the French physiologist Étienne-Émile Baulieu and refers to steroids synthesized in the brain.[3][4] The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an endocrine gland, that then reach the brain through the bloodstream and have effects on brain function.[5] The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on gene expression via nuclear steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy[6] and traumatic brain injury.[7][8] Ganaxolone, a synthetic analog of the endogenous neurosteroid allopregnanolone, is under investigation for the treatment of epilepsy.[9]

Classification

Based on differences in activity and structure, neurosteroids can be broadly categorized into several different major groupings.[3]

Inhibitory neurosteroids

These neurosteroids exert inhibitory actions on neurotransmission. They act as positive allosteric modulators of the GABAA receptor (especially δ subunit-containing isoforms), and possess, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[10] prosocial,[11] antiaggressive,[12] prosexual,[11] sedative, pro-sleep,[13] cognitive and memory-impairing,[citation needed] analgesic,[14] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.[3]

Major examples include tetrahydrodeoxycorticosterone (THDOC), the androstane 3α-androstanediol, the cholestane cholesterol and the pregnanes pregnanolone (eltanolone), allopregnanolone (3α,5α-THP).[15][16]

Excitatory neurosteroids

These neurosteroids have excitatory effects on neurotransmission. They act as potent negative allosteric modulators of the GABAA receptor, weak positive allosteric modulators of the NMDA receptor, and/or agonists of the σ1 receptor, and mostly have antidepressant, anxiogenic, cognitive and memory-enhancing, convulsant, neuroprotective, and neurogenic effects.[3]

Major examples include the pregnanes pregnenolone sulfate (PS), epipregnanolone, and isopregnanolone (sepranolone), the androstanes dehydroepiandrosterone (DHEA; prasterone), and dehydroepiandrosterone sulfate (DHEA-S; prasterone sulfate), and the cholestane 24(S)-hydroxycholesterol (NMDA receptor-selective; very potent).[17]

Pheromones

Pheromones are neurosteroids that influence brain activity, notably hypothalamic function, via activation of vomeronasal receptor cells.[18][19][20]

Possible human pheromones include the androstanes androstadienol, androstadienone, androstenol, and androstenone and the estrane estratetraenol.

Other neurosteroids

Certain other endogenous steroids, such as pregnenolone,[21] progesterone,[22][23] estradiol,[5] and corticosterone are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABAA or NMDA receptors, and instead affect various other cell surface receptors and non-genomic targets. Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone, deoxycorticosterone, DHEA, and testosterone, are metabolized into (other) neurosteroids, effectively functioning as so-called proneurosteroids.

Biosynthesis

Neurosteroids are synthesized from cholesterol, which is converted into pregnenolone and then into all other endogenous steroids. Neurosteroids are produced in the brain after local synthesis or by conversion of peripherally-derived adrenal steroids or gonadal steroids. They accumulate especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources.[24][25] 5α-reductase type I and 3α-hydroxysteroid dehydrogenase are involved in the biosynthesis of inhibitory neurosteroids, while 3β-hydroxysteroid dehydrogenase and hydroxysteroid sulfotransferases are involved in excitatory neurosteroid production.[3]

Function

Some major known biological functions of neurosteroids include modulation of neural plasticity,[26] learning and memory processes,[27] behavior,[28][29] and seizure susceptibility,[30] as well as responses to stress, anxiety, and depression.[11][31] Neurosteroids also appear to play an important role in various sexually-dimorphic behaviors and emotional responses.[29]

Acute stress elevates the levels of inhibitory neurosteroids like allopregnanolone, and these neurosteroids are known to counteract many of the effects of stress.[32] This is similar to the case of endorphins, which are released in response to stress and physical pain and counteract the negative subjective effects of such states. As such, it has been suggested that one of the biological functions of these neuromodulators may be to help maintain emotional homeostasis.[28][33] Chronic stress has been associated with diminished levels of allopregnanolone and altered allopregnanolone stress responsivity, psychiatric disorders, and hypothalamic-pituitary-adrenal axis dysregulation.[31][32]

It is thought that fluctuations in the levels of inhibitory neurosteroids during the menstrual cycle and pregnancy play an important role in a variety of women's conditions, including premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), postpartum depression (PPD), postpartum psychosis, and catamenial epilepsy.[34][35][36] In addition, it is thought that changes in neurosteroid levels may be involved in the changes in mood, anxiety, and sexual desire that occur during puberty in both sexes and during menopause in women.[3][37][38]

Elevated levels of inhibitory neurosteroids, namely allopregnanolone, can produce paradoxical effects, such as negative mood, anxiety, irritability, and aggression.[39][40][41][42] This appears to be because these neurosteroids, like other positive allosteric modulators of the GABAA receptor such as the benzodiazepines, barbiturates, and ethanol,[34][42] possess biphasic, U-shaped actions – moderate levels (in the range of 1.5–2 nM/L total alloprogesterone, which are approximately equivalent to luteal phase levels) inhibit the activity of the GABAA receptor, while lower and higher concentrations facilitate the activity of the receptor.[40][41]

Biological activity

Sigma-1 receptor

Neurosteroids at the σ1 receptor[43]
Compound Ki (nM) Action Species Ref
Deoxycorticosterone 938 Unknown Guinea pig [44][45]
Testosterone 1,014 Unknown Guinea pig [44][45]
Pregnenolone ND Agonist ND ND
Pregnenolone sulfate 3,198 Agonist Guinea pig [44][45]
DHEA 3,700 Agonist ? [45]
DHEA-S ND Agonist ND ND
Corticosterone 4,074 Unknown Guinea pig [44]

Therapeutic applications

Older clinically used synthetic neuroactive steroids.

Anesthesia

Several synthetic neurosteroids have been used as sedatives for the purpose of general anaesthesia for carrying out surgical procedures. The best known of these are alphaxolone, alphadolone, hydroxydione, and minaxolone. The first of these to be introduced was hydroxydione, which is the esterified 21-hydroxy derivative of 5β-pregnanedione. Hydroxydione proved to be a useful anaesthetic drug with a good safety profile, but was painful and irritating when injected probably due to poor water solubility. This led to the development of newer neuroactive steroids. The next drug from this family to be marketed was a mixture of alphaxolone and alphadolone, known as Althesin. This was withdrawn from human use due to rare but serious toxic reactions, but is still used in veterinary medicine. The next neurosteroid anaesthetic introduced into human medicine was the newer drug minaxolone, which is around three times more potent than althesin and retains the favourable safety profile, without the toxicity problems seen with althesin. However this drug was also ultimately withdrawn, not because of problems in clinical use, but because animal studies suggested potential carcinogenicity and since alternative agents were available it was felt that the possible risk outweighed the benefit of keeping the drug on the market.

Ganaxolone

Ganaxolone, a neuroactive steroid currently in clinical development.

The neurosteroid ganaxolone, an analog of the progesterone metabolite allopregnanolone, has been extensively investigated in animal models and is currently in clinical trials for the treatment of epilepsy. Neurosteroids, including ganaxolone have a broad spectrum of activity in animal models.[46] They may have advantages over other GABAA receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.[47][48]

A randomized, placebo controlled, 10-week phase 2 clinical trial of orally administered ganaxolone in adults with partial onset seizure demonstrated that the treatment is safe, well tolerated and efficacious.[9] The drug continued to demonstrate efficacy in a 104-week open label extension. Data from non-clinical studies suggest that ganaxolone may have low risk for use in pregnancy. In addition to use in the treatment of epilepsy, the drug has potential in the treatment of a broad range of neurological and psychiatric conditions. Proof-of-concept studies are currently underway in posttraumatic stress disorder and fragile X syndrome. Ganaxolone was approved for medical use in the United States in March 2022.

Catamenial epilepsy

Researchers have suggested the use of so-called "neurosteroid replacement therapy" as a way of treating catamenial epilepsy with neuroactive steroids such as ganaxolone during the period of the menstrual cycle when seizure frequency increases.[6] Micronized progesterone, which behaves reliably as a prodrug to allopregnanolone, has been suggested as a treatment for catamenial epilepsy in the same manner.[49]

Allopregnanolone

Allopregnanolone (SAGE-547) is under development as an intravenous therapy for the treatment of super-refractory status epilepticus, postpartum depression, and essential tremor.[50]

Other applications

4,16-Androstadien-3β-ol (PH94B, Aloradine) is a synthetic pheromone, or pherine, neurosteroid which is under investigation for the treatment of anxiety disorders in women.[19][20][51]

3β-Methoxypregnenolone (MAP-4343), or pregnenolone 3β-methyl ether, is a synthetic neuroactive steroid and pregnenolone derivative that interacts with microtubule-associated protein 2 (MAP2) in a similar manner to pregnenolone and is under development for potential clinical use for indications such as the treatment of brain and spinal cord injury and depressive disorders.[52][53][54][55]

Role in antidepressant action

Certain antidepressant drugs such as fluoxetine and fluvoxamine, which are generally thought to affect depression by acting as selective serotonin reuptake inhibitors (SSRIs), have also been found to normalize the levels of certain neurosteroids (which are frequently deficient in depressed patients) at doses that are inactive in affecting the reuptake of serotonin. This suggests that other actions involving neurosteroids may also be at play in the effectiveness of these drugs against depression.[56][57]

Benzodiazepine effects on neurosteroids

Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on translocator protein (TSPO; "peripheral benzodiazepine receptor").[58] The pharmacological actions of benzodiazepines at the GABAA receptor are similar to those of neurosteroids. Factors which affect the ability of individual benzodiazepines to alter neurosteroid levels may depend upon whether the individual benzodiazepine drug interacts with TSPO. Some benzodiazepines may also inhibit neurosteroidogenic enzymes reducing neurosteroid synthesis.[59]

See also

References

  1. ↑ "Neuroactive steroids". FASEB Journal 6 (6): 2311–22. March 1992. doi:10.1096/fasebj.6.6.1347506. PMID 1347506. 
  2. ↑ "Neuroactive steroid actions at the GABAA receptor". Hormones and Behavior 28 (4): 537–44. December 1994. doi:10.1006/hbeh.1994.1052. PMID 7729823. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Neurosteroids". Sex Differences in the Human Brain, their Underpinnings and Implications. Progress in Brain Research. 186. 2010. pp. 113–37. doi:10.1016/B978-0-444-53630-3.00008-7. ISBN 9780444536303. 
  4. ↑ "Neurosteroids — Endogenous Regulators of Seizure Susceptibility and Role in the Treatment of Epilepsy". Jasper's Basic Mechanisms of the Epilepsies [Internet]. 4th edition. Bethesda (MD): National Center for Biotechnology Information (US). National Center for Biotechnology Information (US). 2012. https://www.ncbi.nlm.nih.gov/books/NBK98218/. 
  5. ↑ 5.0 5.1 "Rapid estrogen signaling in the brain: implications for the fine-tuning of neuronal circuitry". The Journal of Neuroscience 31 (45): 16056–63. November 2011. doi:10.1523/JNEUROSCI.4097-11.2011. PMID 22072656. 
  6. ↑ 6.0 6.1 "Neurosteroid replacement therapy for catamenial epilepsy". Neurotherapeutics 6 (2): 392–401. April 2009. doi:10.1016/j.nurt.2009.01.006. PMID 19332335. 
  7. ↑ "Recent developments in the significance and therapeutic relevance of neuroactive steroids--Introduction to the special issue". Pharmacology & Therapeutics 116 (1): 1–6. October 2007. doi:10.1016/j.pharmthera.2007.04.003. PMID 17531324. 
  8. ↑ "Steroids, neuroactive steroids and neurosteroids in psychopathology". Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2): 169–92. February 2005. doi:10.1016/j.pnpbp.2004.11.001. PMID 15694225. 
  9. ↑ 9.0 9.1 "Progress report on new antiepileptic drugs: a summary of the Eleventh Eilat Conference (EILAT XI)". Epilepsy Research 103 (1): 2–30. Jan 2013. doi:10.1016/j.eplepsyres.2012.10.001. PMID 23219031. 
  10. ↑ "The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens". The European Journal of Neuroscience 16 (1): 169–73. July 2002. doi:10.1046/j.1460-9568.2002.02084.x. PMID 12153544. 
  11. ↑ 11.0 11.1 11.2 "Neurosteroids' effects and mechanisms for social, cognitive, emotional, and physical functions". Psychoneuroendocrinology 34 (Suppl 1): S143-61. December 2009. doi:10.1016/j.psyneuen.2009.07.005. PMID 19656632. 
  12. ↑ "Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior". Proceedings of the National Academy of Sciences of the United States of America 102 (6): 2135–40. February 2005. doi:10.1073/pnas.0409643102. PMID 15677716. Bibcode: 2005PNAS..102.2135P. 
  13. ↑ "Steroid hormones and sleep regulation". Mini Reviews in Medicinal Chemistry 12 (11): 1040–8. October 2012. doi:10.2174/138955712802762167. PMID 23092405. 
  14. ↑ "Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain". Progress in Neurobiology 113: 70–8. February 2014. doi:10.1016/j.pneurobio.2013.07.004. PMID 23948490. 
  15. ↑ "A predicted binding site for cholesterol on the GABAA receptor". Biophysical Journal 106 (9): 1938–1949. May 2014. doi:10.1016/j.bpj.2014.03.024. PMID 24806926. Bibcode: 2014BpJ...106.1938H. 
  16. ↑ "Cholesterol binding to ion channels". Frontiers in Physiology 5: 65. 2014. doi:10.3389/fphys.2014.00065. PMID 24616704. 
  17. ↑ "The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors". The Journal of Neuroscience 33 (44): 17290–17300. October 2013. doi:10.1523/JNEUROSCI.2619-13.2013. PMID 24174662. 
  18. ↑ The Neurology of Olfaction. Cambridge University Press. 12 February 2009. pp. 37–. ISBN 978-0-521-68216-9. https://books.google.com/books?id=aoE9-GKuhnIC&pg=PA37. 
  19. ↑ 19.0 19.1 "The human vomeronasal system". Psychoneuroendocrinology 19 (5–7): 673–86. 1994. doi:10.1016/0306-4530(94)90049-3. PMID 7938363. 
  20. ↑ 20.0 20.1 "Effect of an acute intranasal aerosol dose of PH94B on social and performance anxiety in women with social anxiety disorder". The American Journal of Psychiatry 171 (6): 675–82. June 2014. doi:10.1176/appi.ajp.2014.12101342. PMID 24700254. https://www.researchgate.net/publication/261511611. 
  21. ↑ "Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence". Neuroscience 191: 78–90. September 2011. doi:10.1016/j.neuroscience.2011.06.076. PMID 21756978. 
  22. ↑ "Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination". Steroids 65 (10–11): 605–12. 2000. doi:10.1016/s0039-128x(00)00173-2. PMID 11108866. 
  23. ↑ "Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells". Neuroendocrinology 96 (2): 162–71. 2012. doi:10.1159/000339822. PMID 22687885. 
  24. ↑ "Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis". Proceedings of the National Academy of Sciences of the United States of America 103 (39): 14602–7. September 2006. doi:10.1073/pnas.0606544103. PMID 16984997. Bibcode: 2006PNAS..10314602A. 
  25. ↑ "Neurosteroids: biochemistry and clinical significance". Trends in Endocrinology and Metabolism 13 (1): 35–43. 2002. doi:10.1016/S1043-2760(01)00503-3. PMID 11750861. 
  26. ↑ "Neurosteroids: endogenous modulators of neuronal excitability and plasticity". Neurology 68 (12): 945–7. March 2007. doi:10.1212/01.wnl.0000257836.09570.e1. PMID 17372131. 
  27. ↑ "Neurosteroids in learning and memory processes". International Review of Neurobiology 46: 273–320. 2001. doi:10.1016/s0074-7742(01)46066-1. ISBN 9780123668462. PMID 11599303. 
  28. ↑ 28.0 28.1 "Neurosteroids and behavior". International Review of Neurobiology 46: 321–48. 2001. doi:10.1016/S0074-7742(01)46067-3. ISBN 9780123668462. PMID 11599304. 
  29. ↑ 29.0 29.1 "Emerging roles for neurosteroids in sexual behavior and function". Journal of Andrology 29 (5): 524–33. 2008. doi:10.2164/jandrol.108.005660. PMID 18567641. 
  30. ↑ "GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids". Experimental Neurology 244: 36–42. June 2013. doi:10.1016/j.expneurol.2011.10.028. PMID 22101060. 
  31. ↑ 31.0 31.1 "Neurosteroids in the context of stress: implications for depressive disorders". Pharmacology & Therapeutics 116 (1): 125–39. October 2007. doi:10.1016/j.pharmthera.2007.05.006. PMID 17597217. 
  32. ↑ 32.0 32.1 "Multifunctional aspects of allopregnanolone in stress and related disorders". Progress in Neuro-Psychopharmacology & Biological Psychiatry 48: 64–78. Jan 2014. doi:10.1016/j.pnpbp.2013.09.005. PMID 24044974. 
  33. ↑ "GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response". Frontiers in Neuroendocrinology 36: 28–48. Jan 2015. doi:10.1016/j.yfrne.2014.06.001. PMID 24929099. 
  34. ↑ 34.0 34.1 "Pathogenesis in menstrual cycle-linked CNS disorders". Annals of the New York Academy of Sciences 1007 (1): 42–53. December 2003. doi:10.1196/annals.1286.005. PMID 14993039. Bibcode: 2003NYASA1007...42B. 
  35. ↑ "The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment". Epilepsy & Behavior 13 (1): 12–24. July 2008. doi:10.1016/j.yebeh.2008.02.004. PMID 18346939. 
  36. ↑ "Female reproductive steroids and neuronal excitability". Neurological Sciences 32 (Suppl 1): S31-5. May 2011. doi:10.1007/s10072-011-0532-5. PMID 21533709. 
  37. ↑ "Neuropeptides, neurotransmitters, neurosteroids, and the onset of puberty". Annals of the New York Academy of Sciences 900 (1): 1–9. 2000. doi:10.1111/j.1749-6632.2000.tb06210.x. PMID 10818386. Bibcode: 2000NYASA.900....1G. 
  38. ↑ "Neuroactive steroids: focus on human brain". Neuroscience 191: 1–5. September 2011. doi:10.1016/j.neuroscience.2011.06.024. PMID 21704130. 
  39. ↑ "Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone". Psychopharmacology 187 (2): 209–21. August 2006. doi:10.1007/s00213-006-0417-0. PMID 16724185. 
  40. ↑ 40.0 40.1 "Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons". Neuroscience 191: 46–54. September 2011. doi:10.1016/j.neuroscience.2011.03.061. PMID 21600269. 
  41. ↑ 41.0 41.1 "Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators". Psychoneuroendocrinology 34 (8): 1121–32. September 2009. doi:10.1016/j.psyneuen.2009.02.003. PMID 19272715. 
  42. ↑ 42.0 42.1 "Allopregnanolone and mood disorders". Progress in Neurobiology 113: 88–94. February 2014. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486. 
  43. ↑ "The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities". Brain Res. Brain Res. Rev. 37 (1–3): 116–32. 2001. doi:10.1016/s0165-0173(01)00112-6. PMID 11744080. 
  44. ↑ 44.0 44.1 44.2 44.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid2832949
  45. ↑ 45.0 45.1 45.2 45.3 Cite error: Invalid <ref> tag; no text was provided for refs named pmid15547787
  46. ↑ Rogawski MA, Reddy DS, 2004. Neurosteroids: endogenous modulators of seizure susceptibility. In: Rho, J.M., Sankar, R., Cavazos, J. (Eds.), Epilepsy: Scientific Foundations of Clinical Practice. Marcel Dekker, New York, 2004;319-355.
  47. ↑ "Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice". The Journal of Pharmacology and Experimental Therapeutics 287 (2): 553–8. November 1998. PMID 9808680. 
  48. ↑ "Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself". The Journal of Pharmacology and Experimental Therapeutics 295 (3): 1241–8. December 2000. PMID 11082461. 
  49. ↑ Complementary and Alternative Therapies for Epilepsy. Demos Medical Publishing. 1 January 2005. pp. 378–. ISBN 978-1-934559-08-6. https://books.google.com/books?id=WVUE-6Xdny4C&pg=PT378. 
  50. ↑ "Brexanolone - Sage Therapeutics". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800039944. 
  51. ↑ "50 years of hurdles and hope in anxiolytic drug discovery". Nature Reviews. Drug Discovery 12 (9): 667–87. September 2013. doi:10.1038/nrd4075. PMID 23989795. PMC 4176700. http://ggriebel.chez-alice.fr/Pub127.pdf. 
  52. ↑ "Pregnenolone methyl ether - Mapreg". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800034216. 
  53. ↑ "Treatment of experimental spinal cord injury with 3β-methoxy-pregnenolone". Brain Res. 1403: 57–66. 2011. doi:10.1016/j.brainres.2011.05.065. PMID 21704982. 
  54. ↑ "3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders". Proc. Natl. Acad. Sci. U.S.A. 109 (5): 1713–8. 2012. doi:10.1073/pnas.1121485109. PMID 22307636. Bibcode: 2012PNAS..109.1713B. 
  55. ↑ "From steroid hormones to depressive states and senile dementias: New mechanistic, therapeutical and predictive approaches". Comptes Rendus Biologies 338 (8–9): 613–6. 2015. doi:10.1016/j.crvi.2015.06.003. PMID 26251072. 
  56. ↑ "Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine". Proceedings of the National Academy of Sciences of the United States of America 95 (6): 3239–44. March 1998. doi:10.1073/pnas.95.6.3239. PMID 9501247. Bibcode: 1998PNAS...95.3239U. 
  57. ↑ "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology 186 (3): 362–72. June 2006. doi:10.1007/s00213-005-0213-2. PMID 16432684. 
  58. ↑ "Role of neurosteroids in the anticonvulsant activity of midazolam". British Journal of Pharmacology 165 (8): 2684–91. April 2012. doi:10.1111/j.1476-5381.2011.01733.x. PMID 22014182. 
  59. ↑ "Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines" (pdf). Biological & Pharmaceutical Bulletin 25 (4): 441–5. April 2002. doi:10.1248/bpb.25.441. PMID 11995921. http://www.jstage.jst.go.jp/article/bpb/25/4/441/_pdf. 

Further reading



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