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 GABA_A 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.

GABA_A Receptor Actions

Certain neurosteroids bind with very high affinity to GABA_A 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 GABA_A 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 GABA_A 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 GABA_A receptors are not completely understood. The GABA_A receptor is a pentameric complex with at least 21 subunit types involved in receptor assembly:

_1-6, ß_1-4,

_1-4,

,

,

,

,

_1-3 (Bonnert et al., 1999; Bormann, 2000; Penschuck et al., 1999). As a result, more than 500,000 different GABA_A 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 GABA_A receptors. For example, benzodiazepines bind to GABA_A 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 GABA_A receptors. In contrast, the neurosteroid allopregnanolone acts at a wide variety of GABA_A receptor subtypes with similar potency and efficacy and does not exhibit stringent GABA_A subunit specificity, possibly reflecting a broad spectrum of action in the central nervous system (Puia et al., 1990).

SSRIs

Recent efforts have linked neurosteroids to selective serotonin reuptake inhibitors. In a clinical study of 15 patients with major depression, cerebrospinal fluid (CSF) levels of the GABAergic neurosteroid allopregnanolone were decreased at baseline compared to control subject levels (Uzunova et al., 1998). Following treatment with fluoxetine (Prozac) or fluvoxamine (Luvox), CSF allopregnanolone levels increased in subjects with depression and correlated strongly with improvements in depressive symptoms. The authors hypothesized that SSRI-induced increases in allopregnanolone may represent a novel mechanism contributing to SSRI efficacy.

Enzyme kinetic studies subsequently demonstrated that fluoxetine, paroxetine (Paxil) and sertraline (Zoloft) increase the efficiency of the enzyme 3

-HSD, which catalyzes allopregnanolone biosynthesis from its immediate precursor 5

-dihydroprogesterone (Griffin and Mellon, 1999), resulting in dramatically enhanced allopregnanolone formation. In addition, allopregnanolone is known to exhibit marked anxiolytic effects in rodents (Crawley et al., 1986; Wieland et al., 1991), consistent with its GABA_A receptor actions. These studies support the possibility that SSRI-induced allopregnanolone biosynthesis may be relevant to SSRI therapeutic actions in depression and anxiety.

Antipsychotic Drug Action

Neurosteroids have also been linked to antipsychotic drug action in recent rodent investigations. For example, the antipsychotic olanzapine (Zyprexa) dose-dependently increases the potent GABAergic neurosteroid allopregnanolone in rat cerebral cortex (Marx et al., 2000a), and preliminary evidence indicates that clozapine (Clozaril) has similar effects (Marx et al., 2001). Since GABAergic neurotransmission appears to be altered in schizophrenia (Lewis, 2000), antipsychotic-induced elevations in allopregnanolone may be relevant to this component of schizophrenia pathophysiology. If olanzapine also induces elevation in allopregnanolone in humans, it is possible that allopregnanolone may contribute to the efficacy of this antipsychotic. Olanzapine also has anxiolytic-like effects in animals (Arnt and Skarsfeldt, 1998), and, therefore, olanzapine-induced elevations in the anxiolytic neurosteroid allopregnanolone may represent a mechanism contributing to these actions. Finally, olanzapine has marked effects on rodent serum progesterone levels, a steroid that appears to have non-reproductive functions in addition to its well-established reproductive actions. For example, recent evidence suggests that progesterone plays an important role in myelination (Baulieu and Schumacher, 2000), a finding that may be relevant to schizophrenia, since recent evidence suggests a dysregulation in myelin-related genes in the disorder (Hakak et al., 2001). Future investigations will be required to determine the potential clinical significance of antipsychotic-induced neurosteroid alterations for schizophrenia pathophysiology and treatment.

Neuroprotection

Many lines of investigation demonstrate that neurosteroids have neuroprotective properties. For example, the GABAergic neurosteroid allopregnanolone demonstrates anticonvulsant effects in a variety of animal seizure models (Belelli et al., 1989; Devaud et al., 1995). A synthetic homologue of the inhibitory neurosteroid pregnanolone sulfate inhibits NMDA-induced current and cell death in rat hippocampal neuronal cultures and significantly reduces cortical and subcortical infarct size in rats (Weaver et al., 1997). The neurosteroid DHEA and its sulfated derivative DHEAS protect rodent embryonic cerebral cortical neurons from anoxia (Marx et al., 2000b), a neurodevelopmental stressor associated with increased schizophrenia risk. DHEA also protects neurons against glutamate and amyloid ß-protein toxicity (Cardounel et al., 1999), glucocorticoid toxicity (Kimonides et al., 1999), and numerous other insults resulting in oxidative stress.

Interestingly, DHEA and DHEAS levels decrease markedly with age in humans, and levels in elderly populations are reduced to 20% to 30% of peak levels in young adulthood (Labrie et al., 1997; Orentreich et al., 1992), but the clinical relevance of this finding has not yet been established. Since DHEA has memory-enhancing effects in animals (Flood et al., 1992; Roberts et al., 1987), it has been hypothesized that DHEA has neuroprotective effects on cognition and that its age-related decline may be related to declining cognitive function with age in the elderly. Since a number of neurosteroids demonstrate prominent neuroprotective effects in a variety of rodent experimental systems, these molecules may function to modulate neuronal insults leading to psychiatric morbidity and merit further exploration in the clinical realm.

The Role of Stress

Several neurosteroids, including allopregnanolone and THDOC, have pronounced effects on the HPA axis. Allopregnanolone decreases corticotropin-releasing factor release from the hypothalamus (Patchev et al., 1994) and also dampens adrenocorticotropin hormone (Patchev et al., 1996) and corticosterone release (Guo et al., 1995; Patchev et al., 1996) in rats. Allopregnanolone is known to increase with stress (Purdy et al., 1991), and, therefore, stress-induced elevations in this neurosteroid would ultimately suppress the HPA axis. It has been hypothesized that stress-induced allopregnanolone induction may therefore represent an endogenous autoregulatory mechanism to restore homeostasis following a stressful event (Morrow et al., 1995).

The GABAergic neurosteroid THDOC also appears to demonstrate HPA axis modulation. Specifically, THDOC appears to be protective against early adverse events in neonatal rats subjected to intermittent maternal deprivation (Patchev et al., 1997). Rats treated with THDOC and exposed to this stressor were protected against HPA axis dysregulation. Since many psychiatric disorders are stress-sensitive and illnesses such as depression demonstrate a dysregulation in stress hormones (including cortisol), neurosteroid modulation of the HPA axis may have important clinical ramifications.

Pharmacological Intervention

Given accumulating evidence suggesting that neurosteroids may be important in psychiatric disorders and treatment strategies, the possibility that neurosteroids (or the enzymes leading to neurosteroid biosynthesis) may serve as targets for pharmacological intervention has received increasing attention. Limiting factors in drug development have included the rapid metabolism and poor water-solubility of neurosteroids, but efforts are currently underway to address these difficulties. For example, the synthetic neurosteroid ganaxolone is a 3ß-methylated analogue of allopregnanolone with more favorable pharmacokinetic properties (Gasior et al., 1999). Similar to allopregnanolone, it demonstrates anticonvulsant efficacy. At this time, it appears likely that neurosteroid drug development initiatives will yield a number of promising compounds to be utilized in the treatment of neuropsychiatric disorders in future years.

Concluding Remarks

Neurosteroids are fascinating molecules with potential relevance to the pathophysiology and treatment of psychiatric disorders. Although future research will be required to characterize the precise roles of neurosteroids in psychiatric illness, current evidence is compelling and justifies further investigations into the actions of these unique compounds in the central nervous system.

Acknowledgements

The author thanks A. Leslie Morrow, Ph.D., and Jeffrey A. Lieberman, M.D., at University of North Carolina for their generous assistance.

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