Neurosteroids and Psychiatric Disorders
Neurosteroids and Psychiatric Disorders
The term neurosteroid refers to steroids formed in the brain. It was created in 1981 by Dr. Etienne-Emile Baulieu and colleagues, following the remarkable discovery that the brain appeared to have the capacity to synthesize its own steroids in situ. In a set of rodent experiments, these researchers determined that the steroid dehydroepiandrosterone sulfate (DHEAS) was present in adult rat brains at concentrations up to 20-fold greater than plasma (Corpechot et al., 1981). Moreover, brain DHEAS concentrations persisted unchanged for over two weeks following adrenalectomy and gonadectomy in these animals, demonstrating that central nervous system DHEAS levels were likely independent of peripheral DHEAS formation in the adrenals or gonads. Hence, the brain itself appeared to be a potential site of steroidogenesis, and subsequent efforts confirmed this possibility. These molecules became known as neurosteroids, since they can be synthesized de novo in the brain from cholesterol or from peripheral steroid precursors that cross the blood-brain barrier readily.
A closely related term, neuroactive steroids, includes steroids formed in the brain and periphery that exhibit rapid actions on neuronal excitability. Unlike classical steroid mechanisms that involve the binding of intracellular receptors and the regulation of gene transcription, neuroactive steroids have nongenomic actions (Paul and Purdy, 1992). Specifically, neuroactive steroids bind to membrane-bound ligand-gated ion channel receptors. As a result, their actions occur very rapidly (over the course of seconds to minutes), in contrast to steroid genomic actions that require hours to days. Interestingly, certain neuroactive steroids with rapid nongenomic effects, such as progesterone, also exhibit traditional genomic steroid actions. Progesterone is considered to be a neurosteroid if it is synthesized in the brain, hence, the terms neurosteroid and neuroactive steroid are often used interchangeably.
Neurosteroids can therefore alter neuronal excitability very rapidly by binding to receptors for inhibitory or excitatory neurotransmitters at the cell membrane. Neurosteroid actions at inhibitory -amino-butyric acid type A (GABAA) receptors are the most extensively characterized to date, but neurosteroid activity has also been demonstrated at excitatory glutamatergic (N-methyl-D-aspartate [NMDA], -amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid [AMPA], kainate), 5-HT3, glycine, sigma type 1 and nicotinic acetylcholine receptors (Rupprecht and Holsboer, 1999). Neurosteroid actions at GABAA receptors can occur at low nanomolar physiologic concentrations, while neurosteroid activity at other receptor types frequently requires higher concentrations of 1.0 x 10-7 M or greater. In addition to the characterization of neurosteroid actions at membrane-bound ligand-gated ion channel receptors, in the last decade it has also been established with certainty that enzymes leading to neurosteroid biosynthesis are present in glia and neurons in the brain (Compagnone and Mellon, 2000). In other words, the enzymatic biosynthetic machinery facilitating steroid formation from cholesterol in peripheral endocrine organs (such as the adrenals, ovaries and testes) is also present in the brain.
Currently, there are relatively few neurosteroid clinical studies, however, converging evidence suggests that these molecules may be relevant to the pathophysiology and pharmacological treatment of psychiatric disorders such as depression and schizophrenia. Specifically, neurosteroids are differentially regulated in males and females and may, therefore, modulate the neurobiology of gender differences observed in a variety of psychiatric illnesses. Neurosteroids are important in neurodevelopment and regulate neuronal cytoarchitecture (Compagnone and Mellon, 1998), suggesting a potential role for these molecules in the pathophysiology of psychiatric disorders demonstrating a neurodevelopmental component and neuronal cytoarchitectural alterations such as schizophrenia. Finally, neurosteroids modulate GABAergic neurotransmission, are linked to antidepressant and antipsychotic drug action, act as neuroprotective agents, modulate the hypothalamic-pituitary-adrenal (HPA) axis, and represent potential targets for pharmacological intervention. These latter neurosteroid properties are discussed below.
GABAA Receptor Actions
Certain neurosteroids bind with very high affinity to GABAA receptors. For example, the neurosteroid 3-hydroxy-5-pregnan-20-one (allopregnanolone) is synthesized by the reduction of progesterone via the enzymes 5-reductase and 3-hydroxysteroid dehydrogenase (3-HSD). Astonishingly, allopregnanolone potentiates GABAergic neurotransmission with 20-fold higher potency than benzodiazepines and 200-fold higher potency than barbiturates (Morrow et al., 1990, 1987). Indeed, the neurosteroid progesterone metabolites allopregnanolone, its stereoisomer 3-hydroxy-5ß-pregnan-20-one (pregnanolone) and the deoxycorticosterone metabolite 3,21-dihydroxy-5-pregnan-20-one (THDOC) are the most potent known modulators of GABAA receptors. Many of the physiologic functions of these endogenous molecules in the human brain remain to be determined, but it is likely that allopregnanolone and other neurosteroids with GABAA receptor activity might play an important role in the regulation of GABA, the major inhibitory neurotransmitter in the mammalian central nervous system.
Neurosteroid interactions with GABAA receptors are not completely understood. The GABAA receptor is a pentameric complex with at least 21 subunit types involved in receptor assembly: 1-6, ß1-4, 1-4, , , , , 1-3 (Bonnert et al., 1999; Bormann, 2000; Penschuck et al., 1999). As a result, more than 500,000 different GABAA receptor subunit combinations are theoretically possible (Lambert et al., 1996). Adding yet another level of molecular complexity, subunit composition appears to determine the pharmacological profile of GABAA receptors. For example, benzodiazepines bind to GABAA receptors but require the presence of a 2 subunit to potentiate GABAergic neurotransmission (Pritchett et al., 1989), suggesting that benzodiazepine activity may be limited to a specific subset of GABAA receptors. In contrast, the neurosteroid allopregnanolone acts at a wide variety of GABAA receptor subtypes with similar potency and efficacy and does not exhibit stringent GABAA subunit specificity, possibly reflecting a broad spectrum of action in the central nervous system (Puia et al., 1990).