Neurosteroid#Inhibitory neurosteroids

{{See also|List of neurosteroids}}

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

These neurosteroids exert inhibitory actions on neurotransmission. They act as positive allosteric modulators of the GABA_A receptor (especially δ subunit-containing isoforms), and possess, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,{{cite journal | vauthors = Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV | title = The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens | journal = The European Journal of Neuroscience | volume = 16 | issue = 1 | pages = 169–73 | date = July 2002 | pmid = 12153544 | doi = 10.1046/j.1460-9568.2002.02084.x | s2cid = 9953445 }} prosocial,{{cite journal | vauthors = Frye CA | title = Neurosteroids' effects and mechanisms for social, cognitive, emotional, and physical functions | journal = Psychoneuroendocrinology | volume = 34 | issue = Suppl 1 | pages = S143-61 | date = December 2009 | pmid = 19656632 | pmc = 2898141 | doi = 10.1016/j.psyneuen.2009.07.005 }} antiaggressive,{{cite journal | vauthors = Pinna G, Costa E, Guidotti A | title = Changes in brain testosterone and allopregnanolone biosynthesis elicit aggressive behavior | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 6 | pages = 2135–40 | date = February 2005 | pmid = 15677716 | pmc = 548579 | doi = 10.1073/pnas.0409643102 | bibcode = 2005PNAS..102.2135P | doi-access = free }} prosexual, sedative, pro-sleep,{{cite journal | vauthors = Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J | title = Steroid hormones and sleep regulation | journal = Mini Reviews in Medicinal Chemistry | volume = 12 | issue = 11 | pages = 1040–8 | date = October 2012 | pmid = 23092405 | doi = 10.2174/138955712802762167 }} cognitive and memory-impairing,{{Citation needed|date=July 2017}} analgesic,{{cite journal | vauthors = Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG | title = Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain | journal = Progress in Neurobiology | volume = 113 | pages = 70–8 | date = February 2014 | pmid = 23948490 | doi = 10.1016/j.pneurobio.2013.07.004 | s2cid = 207407077 }} anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.

Major examples include tetrahydrodeoxycorticosterone (THDOC), the androstane 3α-androstanediol, the cholestane cholesterol and the pregnanes pregnanolone (eltanolone), allopregnanolone (3α,5α-THP).{{cite journal | vauthors = Hénin J, Salari R, Murlidaran S, Brannigan G | title = A predicted binding site for cholesterol on the GABAA receptor | journal = Biophysical Journal | volume = 106 | issue = 9 | pages = 1938–1949 | date = May 2014 | pmid = 24806926 | pmc = 4017285 | doi = 10.1016/j.bpj.2014.03.024 | bibcode = 2014BpJ...106.1938H }}{{cite journal | vauthors = Levitan I, Singh DK, Rosenhouse-Dantsker A | title = Cholesterol binding to ion channels | journal = Frontiers in Physiology | volume = 5 | pages = 65 | year = 2014 | pmid = 24616704 | pmc = 3935357 | doi = 10.3389/fphys.2014.00065 | doi-access = free }}

These neurosteroids have excitatory effects on neurotransmission. They act as potent negative allosteric modulators of the GABA_A 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.

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).{{cite journal | vauthors = Paul SM, Doherty JJ, Robichaud AJ, Belfort GM, Chow BY, Hammond RS, Crawford DC, Linsenbardt AJ, Shu HJ, Izumi Y, Mennerick SJ, Zorumski CF | display-authors = 6 | title = The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-D-aspartate receptors | journal = The Journal of Neuroscience | volume = 33 | issue = 44 | pages = 17290–17300 | date = October 2013 | pmid = 24174662 | pmc = 3812502 | doi = 10.1523/JNEUROSCI.2619-13.2013 }}

{{Main|Pheromone#Axillary steroids}}

Pheromones are neurosteroids that influence brain activity, notably hypothalamic function, via activation of vomeronasal receptor cells.{{cite book| vauthors = Hawkes CH, Doty RL |title=The Neurology of Olfaction|url=https://books.google.com/books?id=aoE9-GKuhnIC&pg=PA37|date=12 February 2009|publisher=Cambridge University Press|isbn=978-0-521-68216-9|pages=37– }}{{cite journal | vauthors = Monti-Bloch L, Jennings-White C, Dolberg DS, Berliner DL | title = The human vomeronasal system | journal = Psychoneuroendocrinology | volume = 19 | issue = 5–7 | pages = 673–86 | year = 1994 | pmid = 7938363 | doi = 10.1016/0306-4530(94)90049-3 | s2cid = 36129626 }}{{cite journal | vauthors = Liebowitz MR, Salman E, Nicolini H, Rosenthal N, Hanover R, Monti L | title = Effect of an acute intranasal aerosol dose of PH94B on social and performance anxiety in women with social anxiety disorder | journal = The American Journal of Psychiatry | volume = 171 | issue = 6 | pages = 675–82 | date = June 2014 | pmid = 24700254 | doi = 10.1176/appi.ajp.2014.12101342 | s2cid = 38510058 | url = https://www.researchgate.net/publication/261511611 }}

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

Certain other endogenous steroids, such as pregnenolone,{{cite journal | vauthors = Marx CE, Bradford DW, Hamer RM, Naylor JC, Allen TB, Lieberman JA, Strauss JL, Kilts JD | title = Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence | journal = Neuroscience | volume = 191 | pages = 78–90 | date = September 2011 | pmid = 21756978 | doi = 10.1016/j.neuroscience.2011.06.076 | s2cid = 26396652 }} progesterone,{{cite journal | vauthors = Baulieu E, Schumacher M | title = Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination | journal = Steroids | volume = 65 | issue = 10–11 | pages = 605–12 | year = 2000 | pmid = 11108866 | doi = 10.1016/s0039-128x(00)00173-2 | s2cid = 14952168 }}{{cite journal | vauthors = Thomas P, Pang Y | title = Membrane progesterone receptors: evidence for neuroprotective, neurosteroid signaling and neuroendocrine functions in neuronal cells | journal = Neuroendocrinology | volume = 96 | issue = 2 | pages = 162–71 | year = 2012 | pmid = 22687885 | pmc = 3489003 | doi = 10.1159/000339822 }} estradiol, and corticosterone are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABA_A 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.

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.{{cite journal | vauthors = Agís-Balboa RC, Pinna G, Zhubi A, Maloku E, Veldic M, Costa E, Guidotti A | title = Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 39 | pages = 14602–7 | date = September 2006 | pmid = 16984997 | pmc = 1600006 | doi = 10.1073/pnas.0606544103 | bibcode = 2006PNAS..10314602A | doi-access = free }}{{cite journal | vauthors = Mellon SH, Griffin LD | title = Neurosteroids: biochemistry and clinical significance | journal = Trends in Endocrinology and Metabolism | volume = 13 | issue = 1 | pages = 35–43 | year = 2002 | pmid = 11750861 | doi = 10.1016/S1043-2760(01)00503-3 | s2cid = 11605131 }} 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.

Some major known biological functions of neurosteroids include modulation of neural plasticity,{{cite journal | vauthors = Benarroch EE | title = Neurosteroids: endogenous modulators of neuronal excitability and plasticity | journal = Neurology | volume = 68 | issue = 12 | pages = 945–7 | date = March 2007 | pmid = 17372131 | doi = 10.1212/01.wnl.0000257836.09570.e1 | s2cid = 219216099 }} learning and memory processes,{{cite journal | vauthors = Vallée M, Mayo W, Koob GF, Le Moal M | title = Neurosteroids in learning and memory processes | journal = International Review of Neurobiology | volume = 46 | pages = 273–320 | year = 2001 | pmid = 11599303 | doi = 10.1016/s0074-7742(01)46066-1 | isbn = 9780123668462 }} behavior,{{cite journal | vauthors = Engel SR, Grant KA | title = Neurosteroids and behavior | journal = International Review of Neurobiology | volume = 46 | pages = 321–48 | year = 2001 | pmid = 11599304 | doi = 10.1016/S0074-7742(01)46067-3| isbn = 9780123668462 }}{{cite journal | vauthors = King SR | title = Emerging roles for neurosteroids in sexual behavior and function | journal = Journal of Andrology | volume = 29 | issue = 5 | pages = 524–33 | year = 2008 | pmid = 18567641 | doi = 10.2164/jandrol.108.005660 | doi-access = free }} and seizure susceptibility,{{cite journal | vauthors = Joshi S, Rajasekaran K, Kapur J | title = GABAergic transmission in temporal lobe epilepsy: the role of neurosteroids | journal = Experimental Neurology | volume = 244 | pages = 36–42 | date = June 2013 | pmid = 22101060 | pmc = 3319002 | doi = 10.1016/j.expneurol.2011.10.028 }} as well as responses to stress, anxiety, and depression.{{cite journal | vauthors = Girdler SS, Klatzkin R | title = Neurosteroids in the context of stress: implications for depressive disorders | journal = Pharmacology & Therapeutics | volume = 116 | issue = 1 | pages = 125–39 | date = October 2007 | pmid = 17597217 | pmc = 2650267 | doi = 10.1016/j.pharmthera.2007.05.006 }} Neurosteroids also appear to play an important role in various sexually-dimorphic behaviors and emotional responses.

Acute stress elevates the levels of inhibitory neurosteroids like allopregnanolone, and these neurosteroids are known to counteract many of the effects of stress.{{cite journal | vauthors = Bali A, Jaggi AS | title = Multifunctional aspects of allopregnanolone in stress and related disorders | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 48 | pages = 64–78 | date = Jan 2014 | pmid = 24044974 | doi = 10.1016/j.pnpbp.2013.09.005 | s2cid = 21399549 }} 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.{{cite journal | vauthors = Gunn BG, Cunningham L, Mitchell SG, Swinny JD, Lambert JJ, Belelli D | title = GABAA receptor-acting neurosteroids: a role in the development and regulation of the stress response | journal = Frontiers in Neuroendocrinology | volume = 36 | pages = 28–48 | date = Jan 2015 | pmid = 24929099 | doi = 10.1016/j.yfrne.2014.06.001 | pmc=4349499}} Chronic stress has been associated with diminished levels of allopregnanolone and altered allopregnanolone stress responsivity, psychiatric disorders, and hypothalamic-pituitary-adrenal axis dysregulation.

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.{{cite journal | vauthors = Bäckström T, Andersson A, Andreé L, Birzniece V, Bixo M, Björn I, Haage D, Isaksson M, Johansson IM, Lindblad C, Lundgren P, Nyberg S, Odmark IS, Strömberg J, Sundström-Poromaa I, Turkmen S, Wahlström G, Wang M, Wihlbäck AC, Zhu D, Zingmark E | title = Pathogenesis in menstrual cycle-linked CNS disorders | journal = Annals of the New York Academy of Sciences | volume = 1007 | issue = 1| pages = 42–53 | date = December 2003 | pmid = 14993039 | doi = 10.1196/annals.1286.005 | bibcode = 2003NYASA1007...42B | s2cid = 20995334 | doi-access = free }}{{cite journal | vauthors = Guille C, Spencer S, Cavus I, Epperson CN | title = The role of sex steroids in catamenial epilepsy and premenstrual dysphoric disorder: implications for diagnosis and treatment | journal = Epilepsy & Behavior | volume = 13 | issue = 1 | pages = 12–24 | date = July 2008 | pmid = 18346939 | pmc = 4112568 | doi = 10.1016/j.yebeh.2008.02.004 }}{{cite journal | vauthors = Finocchi C, Ferrari M | title = Female reproductive steroids and neuronal excitability | journal = Neurological Sciences | volume = 32 | issue = Suppl 1 | pages = S31-5 | date = May 2011 | pmid = 21533709 | doi = 10.1007/s10072-011-0532-5 | s2cid = 8885335 }} 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.{{cite journal | vauthors = Genazzani AR, Bernardi F, Monteleone P, Luisi S, Luisi M | title = Neuropeptides, neurotransmitters, neurosteroids, and the onset of puberty | journal = Annals of the New York Academy of Sciences | volume = 900 | issue = 1| pages = 1–9 | year = 2000 | pmid = 10818386 | doi = 10.1111/j.1749-6632.2000.tb06210.x | bibcode = 2000NYASA.900....1G | s2cid = 19302118 }}{{cite journal | vauthors = Melcangi RC, Panzica G, Garcia-Segura LM | title = Neuroactive steroids: focus on human brain | journal = Neuroscience | volume = 191 | pages = 1–5 | date = September 2011 | pmid = 21704130 | doi = 10.1016/j.neuroscience.2011.06.024 | hdl = 10261/61590 | s2cid = 55704799 | hdl-access = free }}

Elevated levels of inhibitory neurosteroids, namely allopregnanolone, can produce paradoxical effects, such as negative mood, anxiety, irritability, and aggression.{{cite journal | vauthors = Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T | title = Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone | journal = Psychopharmacology | volume = 187 | issue = 2 | pages = 209–21 | date = August 2006 | pmid = 16724185 | doi = 10.1007/s00213-006-0417-0 | s2cid = 1933116 }}{{cite journal | vauthors = Bäckström T, Haage D, Löfgren M, Johansson IM, Strömberg J, Nyberg S, Andréen L, Ossewaarde L, van Wingen GA, Turkmen S, Bengtsson SK | title = Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons | journal = Neuroscience | volume = 191 | pages = 46–54 | date = September 2011 | pmid = 21600269 | doi = 10.1016/j.neuroscience.2011.03.061 | s2cid = 38928854 }}{{cite journal | vauthors = Andréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T | title = Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators | journal = Psychoneuroendocrinology | volume = 34 | issue = 8 | pages = 1121–32 | date = September 2009 | pmid = 19272715 | doi = 10.1016/j.psyneuen.2009.02.003 | s2cid = 22259026 }}{{cite journal | vauthors = Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G | title = Allopregnanolone and mood disorders | journal = Progress in Neurobiology | volume = 113 | pages = 88–94 | date = February 2014 | pmid = 23978486 | doi = 10.1016/j.pneurobio.2013.07.005 | s2cid = 207407084 }} This appears to be because these neurosteroids, like other positive allosteric modulators of the GABA_A receptor such as the benzodiazepines, barbiturates, and ethanol, 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 GABA_A receptor, while lower and higher concentrations facilitate the activity of the receptor.

File:Neuroactive steroids.png

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.

File:Ganaxolone.svg

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.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. They may have advantages over other GABA_A receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.{{cite journal | vauthors = Kokate TG, Yamaguchi S, Pannell LK, Rajamani U, Carroll DM, Grossman AB, Rogawski MA | title = Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 287 | issue = 2 | pages = 553–8 | date = November 1998 | doi = 10.1016/S0022-3565(24)37827-9 | pmid = 9808680 }}{{cite journal | vauthors = Reddy DS, Rogawski MA | title = Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 295 | issue = 3 | pages = 1241–8 | date = December 2000 | doi = 10.1016/S0022-3565(24)39026-3 | pmid = 11082461 }}

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. 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.

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.{{cite journal | vauthors = Reddy DS, Rogawski MA | title = Neurosteroid replacement therapy for catamenial epilepsy | journal = Neurotherapeutics | volume = 6 | issue = 2 | pages = 392–401 | date = April 2009 | pmid = 19332335 | pmc = 2682439 | doi = 10.1016/j.nurt.2009.01.006 }} Micronized progesterone, which behaves reliably as a prodrug to allopregnanolone, has been suggested as a treatment for catamenial epilepsy in the same manner.{{cite book | vauthors = Devinsky O, Schachter S, Pacia S | title = Complementary and Alternative Therapies for Epilepsy | url = https://books.google.com/books?id=WVUE-6Xdny4C&pg=PT378 | date = 1 January 2005 | publisher = Demos Medical Publishing | isbn = 978-1-934559-08-6 | pages = 378– }}

Allopregnanolone (SAGE-547) is under development as an intravenous therapy for the treatment of super-refractory status epilepticus, postpartum depression, and essential tremor.{{Cite web|url=http://adisinsight.springer.com/drugs/800039944|title = Brexanolone - Sage Therapeutics | work = AdisInsight | publisher = Springer Nature Switzerland AG }}

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.{{cite journal | vauthors = Griebel G, Holmes A | title = 50 years of hurdles and hope in anxiolytic drug discovery | journal = Nature Reviews. Drug Discovery | volume = 12 | issue = 9 | pages = 667–87 | date = September 2013 | pmid = 23989795 | doi = 10.1038/nrd4075 | url = http://ggriebel.chez-alice.fr/Pub127.pdf | pmc=4176700}}

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.{{Cite web|url=http://adisinsight.springer.com/drugs/800034216|title = Pregnenolone methyl ether - Mapreg | work = AdisInsight | publisher = Springer Nature Switzerland AG }}{{cite journal | vauthors = Duchossoy Y, David S, Baulieu EE, Robel P | title = Treatment of experimental spinal cord injury with 3β-methoxy-pregnenolone | journal = Brain Res. | volume = 1403 | pages = 57–66 | year = 2011 | pmid = 21704982 | doi = 10.1016/j.brainres.2011.05.065 | s2cid = 42657539 }}{{cite journal | vauthors = Bianchi M, Baulieu EE | title = 3β-Methoxy-pregnenolone (MAP4343) as an innovative therapeutic approach for depressive disorders | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 109 | issue = 5 | pages = 1713–8 | year = 2012 | pmid = 22307636 | pmc = 3277154 | doi = 10.1073/pnas.1121485109 | bibcode = 2012PNAS..109.1713B | doi-access = free }}{{cite journal | vauthors = Baulieu ÉÉ | title = From steroid hormones to depressive states and senile dementias: New mechanistic, therapeutical and predictive approaches | journal = Comptes Rendus Biologies | volume = 338 | issue = 8–9 | pages = 613–6 | year = 2015 | pmid = 26251072 | doi = 10.1016/j.crvi.2015.06.003 | doi-access = free }}

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.{{cite journal | vauthors = Uzunova V, Sheline Y, Davis JM, Rasmusson A, Uzunov DP, Costa E, Guidotti A | title = Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 6 | pages = 3239–44 | date = March 1998 | pmid = 9501247 | pmc = 19726 | doi = 10.1073/pnas.95.6.3239 | bibcode = 1998PNAS...95.3239U | doi-access = free }}{{cite journal | vauthors = Pinna G, Costa E, Guidotti A | title = Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake | journal = Psychopharmacology | volume = 186 | issue = 3 | pages = 362–72 | date = 24 January 2006 | pmid = 16432684 | doi = 10.1007/s00213-005-0213-2 | s2cid = 7799814 }}

The 3α-hydroxysteroid dehydrogenase (3α-HSD) enzyme is induced by certain (SSRIs), including fluoxetine, fluvoxamine, sertraline, and paroxetine, as well as by certain other antidepressants like venlafaxine and mirtazapine, and these antidepressants have been found to increase inhibitory neurosteroid levels.{{cite book|last1=Reddy|first1=Doodipala Samba|title=Sex Differences in the Human Brain, their Underpinnings and Implications|chapter=Neurosteroids|volume=186|year=2010|pages=113–137|issn=0079-6123|doi=10.1016/B978-0-444-53630-3.00008-7|pmid=21094889|pmc=3139029|series=Progress in Brain Research|isbn=978-0-444-53630-3}}{{cite journal |vauthors=Griffin LD, Mellon SH | title = Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 23 | pages = 13512–7 | date = November 1999 | pmid = 10557352 | pmc = 23979 | doi = 10.1073/pnas.96.23.13512 | bibcode = 1999PNAS...9613512G | doi-access = free }}{{cite journal | author = Pinna G | title = In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis | journal = Behav Pharmacol | volume = 21 | issue = 5–6 | pages = 438–50 | date = September 2010 | pmid = 20716970 | pmc = 2942072 | doi = 10.1097/FBP.0b013e32833d8ba0 }}{{cite journal |vauthors=Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R | title = Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity | journal = Mol. Psychiatry | volume = 11 | issue = 3 | pages = 261–72 | date = March 2006 | pmid = 16344854 | doi = 10.1038/sj.mp.4001782 | s2cid = 21473462 | doi-access = }} Enhancement of biosynthesis of inhibitory neurosteroids has been implicated in the antidepressant and anxiolytic effects of some of the SSRIs.

Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on translocator protein (TSPO; "peripheral benzodiazepine receptor").{{cite journal | vauthors = Dhir A, Rogawski MA | title = Role of neurosteroids in the anticonvulsant activity of midazolam | journal = British Journal of Pharmacology | volume = 165 | issue = 8 | pages = 2684–91 | date = April 2012 | pmid = 22014182 | pmc = 3423249 | doi = 10.1111/j.1476-5381.2011.01733.x }} The pharmacological actions of benzodiazepines at the GABA_A receptor are similar to those of neurosteroids, although the localization of benzodiazepine and neurosteroid-sensitive GABA_A receptor subtypes vary.{{Cite journal |last=Wang |first=Mingde |date=2011 |title=Neurosteroids and GABA-A Receptor Function |journal=Frontiers in Endocrinology |volume=2 |pages=44 |doi=10.3389/fendo.2011.00044 |doi-access=free |issn=1664-2392 |pmc=3356040 |pmid=22654809}} 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.{{cite journal | vauthors = Usami N, Yamamoto T, Shintani S, Ishikura S, Higaki Y, Katagiri Y, Hara A | title = Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines | journal = Biological & Pharmaceutical Bulletin | volume = 25 | issue = 4 | pages = 441–5 | date = April 2002 | pmid = 11995921 | doi = 10.1248/bpb.25.441 | url = http://www.jstage.jst.go.jp/article/bpb/25/4/441/_pdf | format = pdf | doi-access = free }}

• List of neurosteroids
• Neurosteroidogenesis inhibitor
• Membrane steroid receptor

{{Reflist}}

{{Refbegin|2}}

• {{cite journal | vauthors = Akk G, Shu HJ, Wang C, Steinbach JH, Zorumski CF, Covey DF, Mennerick S | title = Neurosteroid access to the GABAA receptor | journal = The Journal of Neuroscience | volume = 25 | issue = 50 | pages = 11605–13 | date = December 2005 | pmid = 16354918 | pmc = 6726021 | doi = 10.1523/JNEUROSCI.4173-05.2005 }}
• {{cite journal | vauthors = Wang JM, Johnston PB, Ball BG, Brinton RD | title = The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression | journal = The Journal of Neuroscience | volume = 25 | issue = 19 | pages = 4706–18 | date = May 2005 | pmid = 15888646 | pmc = 6724768 | doi = 10.1523/JNEUROSCI.4520-04.2005 }}
• {{cite journal | vauthors = Dong E, Matsumoto K, Uzunova V, Sugaya I, Takahata H, Nomura H, Watanabe H, Costa E, Guidotti A | title = Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 5 | pages = 2849–54 | date = February 2001 | pmid = 11226329 | pmc = 30228 | doi = 10.1073/pnas.051628598 | bibcode = 2001PNAS...98.2849D | doi-access = free }}
• {{cite journal | vauthors = Melcangi RC, Celotti F, Martini L | title = Progesterone 5-alpha-reduction in neuronal and in different types of glial cell cultures: type 1 and 2 astrocytes and oligodendrocytes | journal = Brain Research | volume = 639 | issue = 2 | pages = 202–6 | date = March 1994 | pmid = 8205473 | doi = 10.1016/0006-8993(94)91731-0 | s2cid = 37105244 }}
• {{cite journal | vauthors = Corpéchot C, Robel P, Axelson M, Sjövall J, Baulieu EE | title = Characterization and measurement of dehydroepiandrosterone sulfate in rat brain | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 8 | pages = 4704–7 | date = August 1981 | pmid = 6458035 | pmc = 320231 | doi = 10.1073/pnas.78.8.4704 | bibcode = 1981PNAS...78.4704C | doi-access = free }}
• {{cite book | vauthors = Reddy D, Rogawski MA | chapter=Neurosteroids — Endogenous regulators of seizure susceptibility and role in the treatment of epilepsy | veditors=Noebels JL, Avoli M, Rogawski MA, et al. |title=Jasper's Basic Mechanisms of the Epilepsies |edition= 4th |location=Bethesda (MD) |publisher=National Center for Biotechnology Information|chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK98218 | year = 2012 | pmid = 22787590 }}

{{Refend}}

{{Steroid hormones}}

{{General anesthetics}}

{{Chemical classes of psychoactive drugs}}

{{Use dmy dates|date=April 2017}}

Category:Neurophysiology