Trends in Neurosciences
ReviewNeuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives
Section snippets
Sources and biosynthesis of neuroactive steroids
Owing to their lipophilic nature, steroids that are produced in various endocrine organs can easily cross the blood–brain barrier. However, a variety of neuroactive steroids can be synthesized in the brain itself without the aid of peripheral sources16. These steroids that are formed within the brain from cholesterol are often defined as ‘neurosteroids’16. Direct evidence for steroid synthesis within the brain has come from experiments that demonstrate the formation of steroids in rat glial
Steroid modulation of GABAA receptors
In 1986, it was shown for the first time that the neuroactive steroids 3α,5α-THP and 3α,5α-THDOC could modulate neuronal excitability via their interaction with GABAA receptors4. These receptors consist of various subunits that form ligand-gated ion channels with considerable homology to glycine, nicotinic acetylcholine and 5-HT3 receptors5, 6, 19. The steroids 3α,5α-THP and 3α,5α-THDOC were able not only to displace t-butylbicyclophosphorothionate (TBPS) from the Cl− channel but also to
Pharmacological effects of neuroactive steroids
The actions of neuroactive steroids at the molecular level provide the basis for their modulation of a broad spectrum of physiological and pathological conditions (Box 1). For example, the NMDA-receptor antagonism produced by estrogens and 3α-reduced pregnane steroids might, in part, account for their neuroprotective properties26, 28. Moreover, in view of the reported memory-enhancing effects of pregnenolone41 and DHEA (Ref. 42) in animal studies, steroids that are negative allosteric
Outlook and perspectives
The term ‘neuroactive steroids’, which was initially adopted for steroids that modulate neuronal excitability via specific interactions with neurotransmitter receptors, has been challenged by the identification of steroid hormones that modulate various neurotransmitter receptors allosterically and by the genomic effects of neuroactive steroids that modulate the GABAA receptor. These observations underline the importance of the intracellular crosstalk between genomic and nongenomic steroid
Acknowledgements
We thank Christian Behl and Bettina Hermann for their critical reading of the manuscript. The work on neuroactive steroids at the Max Planck Institute of Psychiatry in Munich is supported by the Gerhard Heβ Programm of the Deutsche Forschungsgemeinschaft to R.R.
References (63)
J. Psychiatr. Res.
(1997)Trends Pharmacol. Sci.
(1995)Trends Pharmacol. Sci.
(1991)- et al.
Front. Neuroendocrinol.
(1996) Neuron
(1993)- et al.
Mol. Brain Res.
(1995) Trends Neurosci.
(1998)Psychoneuroendocrinology
(1998)Neuron
(1990)Brain Res.
(1997)
Brain Res.
Neuroscience
Brain Res.
Am. J. Obstet. Gynecol.
Brain Res.
Brain Res.
Neurosci. Biobehav. Rev.
Eur. J. Obstet. Gynecol. Reprod. Biol.
Science
Endocrine Rev.
Science
FASEB J.
FASEB J.
Science
Annu. Rev. Physiol.
Mol. Pharmacol.
J. Clin. Endocrinol. Metab.
Front. Neuroendocrinol.
Mol. Endocrinol.
Proc. Natl. Acad. Sci. U. S. A.
J. Pharmacol. Exp. Ther.
Cited by (611)
5β-reduced neuroactive steroids as modulators of growth and viability of postnatal neurons and glia
2024, Journal of Steroid Biochemistry and Molecular BiologyThe insula mediates the effects of glucocorticoids in anxiety
2023, NeuropharmacologyNeurosteroid influence on affective tone
2023, Neuroscience and Biobehavioral ReviewsMechanism of action and neurotoxic effects of chronic exposure to bisphenol F in adult zebrafish
2022, Science of the Total Environment