Neurosteroid - Wikipedia
Anxiety disorders are the most common psychiatric disorders. They are frequently treated with benzodiazepines, which are fast acting highly effective anxiolytic agents. However, their long-term use is impaired by tolerance development and abuse liability. In contrast, antidepressants such as selective serotonin reuptake inhibitors SSRIs are considered as first-line treatment but have a slow onset of action.
However, they also modulate sigma receptors and they are modulated themselves by SSRIs. Both pre-clinical and clinical studies have shown that neurosteroid homeostasis is altered in depression and anxiety disorders and antidepressants may act in part through restoring neurosteroid disbalance.
Thus, neurosteroids are important endogenous neuromodulators for the physiology and pathophysiology of anxiety and they may constitute a novel therapeutic approach in the treatment of these disorders. Anxiety disorders are among the most common mental health conditions, which cause significant functional impairments, and frequently turn into chronic clinical conditions Nutt et al. Recent epidemiological findings suggest them as the most frequent class of mental disorders with a high degree of comorbidity with other medical and psychiatric conditions Kessler et al.
Both pharmacotherapy and psychotherapy are effective treatments for anxiety disorders. First-line treatments are the selective serotonin reuptake inhibitors SSRIs that display their anxiolytic effects after several weeks of treatment Baldwin and Nair, ; Bandelow et al.
On the other hand, benzodiazepines BDZs are fast acting and effective antianxiety agents and the most commonly used anxiolytic agents. Thus, NS represent promising compounds modulating both the pathophysiology and the pharmacotherapy of anxiety disorders.
Here, we provide a review of the different actions of NS and discuss the evidence given by pre-clinical and clinical data. In the brain, it is synthesized from progesterone by the sequential action of two enzymes: The figure shows the chemical structures of the main NS involved in this pathway.
Deficient serotonergic neurotransmission in various brain regions is thought to be involved in the development of depression and anxiety disorders Nordquist and Oreland, A Schematic model of the serotonin transporter and the molecule structure of serotonin 5-HT. The development of the SSRIs represents an important advance in the pharmacotherapy of psychiatric disorders Baldwin et al. SSRIs inhibit the reuptake of serotonin into the presynaptic nerve terminal, thereby increasing 5-HT concentrations in the synaptic cleft and prolonging its activity at postsynaptic receptor sites.
The 5HT 1A receptor is a somatodendritic autoreceptor. Its activation results in a decreased firing activity along the serotonergic axon with a consequent enhancement of the serotonergic neurotransmission Castro et al. From the development of the serotonin transporter knockout mice Mathews et al. Of the 18 serotonin receptor subtypes so far characterized in the CNS Raymond et al. For example, long-term fluoxetine treatment modulates the cannabinoid type-1 receptor action through 5HT 1A receptor-dependent mechanisms Mato et al.
Fluoxetine, a selective SSRIs inhibitor is also a modulator of neurosteroidogenesis in the brain Pinna et al. Early studies by Steiner et al. Therefore, it may be argued that the mere blockade of the 5-HT uptake by fluoxetine might not be sufficient to explain its ability to counteract impulsiveness, anxiety, panic, and mood disturbances.
On the other hand, the anxiolytic actions of fluoxetine might be explained by its ability to increase brain neurosteroid content which, in turn, can modulate GABAergic neurotransmission. Sigma receptors were first described as a subclass of the opioid receptors Martin et al. Two different receptors have been characterized, sigma-1 and sigma-2 receptors that display different drug selectivity and molecular mass Hellewell and Bowen, They can bind various exogenous ligands of quite different structural classes, and with different therapeutic and pharmacological profiles Cobos et al.
Neurosteroids are considered the most probable candidates as endogenous ligands of the sigma-1 receptor for a comprehensive review see Monnet and Maurice, Specifically, while pregnenolone, dehydroepiandrosterone DHEA and their sulfate esters act as agonists of the sigma-1 receptors, progesterone acts as a potent antagonist Monnet et al. These effects were all attenuated by the sigma-1 antagonist NE In particular, the efficacy of sigma-1 receptor agonists is inversely correlated with the concentration of endogenous progesterone.
An important aspect to consider is the concurrent modulation of the hypothalamic-pituitary—adrenal HPA axis by NS and sigma ligands, the biological system that has been most closely linked to the stress response in mammals. HPA axis activity is controlled by the amygdala and the hippocampus.
Stressors acting on the amygdala stimulate the hypothalamus and potentially the HPA axis, which in turn results in cortisol production by the adrenal gland. Cortisol binds to glucocorticoid and mineralocorticoid receptors in the hippocampus and, through a negative feed-back loop, suppresses hypothalamic activity, and restores homeostasis.
Stress, in turn, has been implicated to be involved in the onset and maintenance of psychiatric disorders. Moreover, psychosocial stressors have been shown to be related to the onset of anxious episodes.
Indeed, the stress- or panic-induced released of NS has been suggested as an endogenous homeostatic mechanism for restoring normal activity of the HPA axis Barbaccia et al. GABA A receptors are one of the most important targets for the treatment of anxiety symptoms, because reduced GABA A receptor function may be related to the pathophysiology of anxiety Nikolaus et al.
GABA A agonists, such as BDZs, are widely used for the acute treatment of anxiety symptoms, such as panic, agitation, tension, hyperarousal, sensation of lack of control, phobia, insomnia, since they exert their efficacy much more quickly than SSRIs Ravindran and Stein, Barbiturates are GABA A agonists as well and have been used in the past in view of their anticonvulsant, anxiolytic, sedative, and hypnotic actions.
However, due to their serious side effects, such as a profound depression of CNS activity with the induction of pronounced sedation and a lethal risk in case of overdose, they are considered obsolete for the treatment of anxiety disorders Smith and Riskin, Moreover, concentrations in the micromolar range of this NS have been shown to exert a certain intrinsic agonistic activity even in the absence of GABA Puia et al.
Reduced-NS concentrations have been reported during experimental panic induction with either CCK-4 or sodium lactate in patients with panic disorders but not in normal subjects, suggesting a decrease of the GABAergic tone during experimentally induced panic attacks in patients with panic disorder Strohle et al.
Indeed, alcohol administration increases the concentration of NS in the brain Barbaccia et al. Alcohol withdrawal symptoms in rats are alleviated by NS Finn et al. Moreover, plasma levels of NS are markedly reduced in alcoholic patients during the early withdrawal phase, which is accompanied by increased anxiety and depression scores Romeo et al. Pharmacological strategies for the treatment of anxiety are not completely satisfying so far.
BDZs offer the clear advantage of being safer and better tolerated than barbiturates i. However, there is still abuse potential for these drugs, which is a considerable problem. Besides the abuse, also the well known tolerance liability reduction in the potency of BDZs as well as amnesia and sedation represent important side effects of BDZs. Therefore, chronic treatment with BDZs is not recommended according to current guidelines Licata and Rowlett, On the other hand, it has been shown that tolerance toward anxiolytic effects is not developed by the GABA A receptor modulating NS pregnanolone with intermittent chronic dosing Kokate et al.
Therefore, neurosteroidogenic agents that lack BDZ-like side effects may be a promising strategy in the treatment of anxiety. Indeed, NS replacement is a potential therapeutic approach, but natural NS have poor bioavailability and may be converted to metabolites with undesired progestational activity. Because of its longer duration of action, ganaxolone might have greater tolerance liability. However, clinical trials with ganaxolone in the treatment of epilepsy have been encouraging and suggest that this NS has a lower propensity for tolerance than BDZs Reddy, Moreover, an alternative to ganaxolone could be the use of drugs that stimulate NS biosynthesis.
Furthermore, drugs acting on the key enzymes i. A growing body of evidence suggests that glutamatergic neurotransmission may also be involved in the biological mechanisms underlying stress response and anxiety-related disorders.
It is well established that NS regulate gene expression genomic effect and can alter neuronal excitability by interacting with specific neurotransmitter receptors Rupprecht and Holsboer, Thus, NS that act as positive allosteric modulators of GABA A receptors have been described as anxiolytic, sedative, and anticonvulsive substances Smith, On the other hand, systemically administered PREGS showed a biphasic effect on anxiety responses depending on the dosage applied in different behavioral tests Melchior and Ritzmann, ; Reddy and Kulkarni, Following cholesterol translocation, pregnenolone, and ring A-reduced neurosteroids are synthesized, which in turn may enhance GABA-mediated neurotransmission Rupprecht and Holsboer, ; Rupprecht et al.
Thus enhancing neurosteroidogenesis, via TSPO ligands may represent a new strategy in the treatment of anxiety for a recent review Rupprecht et al. A decrease in TSPO expression on platelets or on lymphocytes has been demonstrated in several anxiety disorders, such as generalized anxiety disorder Ferrarese et al.
More recently, Verleye et al. In membrane preparations from intact male rat forebrain, they demonstrated that etifoxine uncompetitively inhibited the binding of the TSPO ligand PK Kita and Furukawa investigated the anxiolytic-like effects of AC, a TSPO ligand, in the social interaction test in mice demonstrating that the anxiolytic-like effects of AC require newly synthesized neurosteroids.
Neurosteroids are powerful modulators within the CNS and they affect numerous neurophysiological processes. They exert their action already at low concentrations and they may act on different neurotransmitter pathways. Their ability to modulate different pathways that also interact with each other makes them interesting candidates for the pharmacotherapy of anxiety disorders, in the case of comorbidity with other mental diseases such as mood disorders.
The new drugs should have good oral bioavailability. NS apparently have less abuse potential than benzodiazepines. Decreased abuse liability together with the lack of interaction with ethanol, might present a potential advantage over currently available benzodiazepine anxiolytics. Moreover, TSPO ligands can promote the production of steroids, restore neurosteroid-mediated neurotransmission in the brain, and thus compensate for anxiety states.
As TSPO levels have been found to be reduced in patients affected by anxiety disorders, the use of ligands to stimulate TSPO steroidogenesis can offer a novel therapeutic strategy for the treatment of anxiety. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
National Center for Biotechnology Information , U. Journal List Front Endocrinol Lausanne v. Published online Oct Prepublished online Aug This article was submitted to Frontiers in Neuroendocrine Science, a specialty of Frontiers in Endocrinology. Received Jul 6; Accepted Oct 3. This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.
This article has been cited by other articles in PMC. Abstract Anxiety disorders are the most common psychiatric disorders. Introduction Anxiety disorders are among the most common mental health conditions, which cause significant functional impairments, and frequently turn into chronic clinical conditions Nutt et al.
Open in a separate window. Serotoninergic System Deficient serotonergic neurotransmission in various brain regions is thought to be involved in the development of depression and anxiety disorders Nordquist and Oreland, Sigma-1 Receptors Sigma receptors were first described as a subclass of the opioid receptors Martin et al.
Conclusion Neurosteroids are powerful modulators within the CNS and they affect numerous neurophysiological processes. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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