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Anxiety/PTSD/OCD: Prozac's Mechanism Of Action Is Normalization Of Allpregnanolone In The Brain

Discussion in 'Mind, Sleep, Stress' started by roguesandy, Jul 5, 2013.

  1. roguesandy

    roguesandy Member

    Joined:
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    This is in response to an email I sent to RP regarding someone that I'm with complicated health issues (had childhood cancer, has PTSD, OCD, high blood pressure, constipation, ED, muscle wasting).

    Something really interesting mentioned in the studies is the mechanism of action behind Prozac and other SSRIs. It has nothing to do with serotonin and everything to do with upregulating pregnenolone, which is 50-60% lower in the spinal fluid of those with anxiety disorders/depression than those without.

    His response:

    -----------------------------------------------------------------------------------------------------

    A daily carrot, for constipation and to lower estrogen and cortisol, thyroid to lower blood pressure, and pregnenolone and DHEA to increase the neurosteroids.

    Compr Psychiatry. 1998 May-Jun;39(3):160-4.
    Efficacy of cyproheptadine for nightmares associated with posttraumatic stress disorder.
    Gupta S, Popli A, Bathurst E, Hennig L, Droney T, Keller P.
    Department of Psychiatry, Olean General Hospital, NY, USA.
    A retrospective review of the psychiatric records of nine patients with posttraumatic stress disorder (PTSD) was conducted to determine the efficacy of cyproheptadine in relieving nightmares. The treatment dose was 4 to 12 mg at bedtime. The response varied from complete remission to a decrease in the intensity and frequency of nightmares.

    Annals of General Psychiatry 2006, 5(Suppl 1):S159
    Effect of cyproheptadine on combat related PTSD nightmares
    Gholamhossien Ahmadzadeh, Ghorbanali Asadolahi, Gavad Mahmodi and Arezoo Farhat
    Behavioral Science Research Center, Khorshid Medical Center Esfahan, Iran
    Background
    Recent studies have shown the role serotonergic system in post-traumatic stress disorder. Trazodone and Nefazodone (5H2 antagonist) amilorated PTSD nightmares but the receptors are mixed. This study promoted an open trial of cyporoheptadine for Iran versus Iraq combat related PTSD patients nightmares.
    Materials and methods
    25 patients studies in 8 week, before after trial of cyproheptadine, the participant were male and chronic PTSD patients with combat related nightmares.
    Results
    5 patients were excluded from the study because of side effects including dizziness and somnolence. 20 patients completed the study. Average nightmare severity decreased from 6.85 to 5.05 which was statistically signifcant (p < 0.01).
    Discussion
    Cyproheptadine may be effective in PTSD nightmare treatment.
    References
    • Harsh HH: Cyorheptatine for recurrent nighmares.
    Am J Psy 1986, 143:1491-1492.



    Mental and Behavioural Disorders and Diseases of the Nervous System » "Anxiety Disorders", book edited by Vladimir Kalinin, ISBN 978-953-307-592-1, Published: August 1, 2011 under CC BY-NC-SA 3.0 license
    Chapter 16
    Neurosteroid Biosynthesis Upregulation: A Novel Promising Therapy for Anxiety Disorders and PTSD
    By Graziano Pinna
    [1] Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, USA

    Overview
    1. Introduction
    2. Neurosteroids modulation of GABAA receptors function
    3. Neurosteroid biosynthesis in corticolimbic neurons
    4. Social isolation induces a selective neuron-specific decrease of 5α-reductase in corticolimbic neurons
    5. GABAergic neurotransmission deficits resulting from allopregnanolone downregulation
    6. Behavioral effects induced by allopregnanolone downregulation in corticolimbic areas
    7. Social isolation induces changes in GABAA receptor subunit expression
    8. Selective brain steroidogenic stimulants (SBSSs) improve behavioral deficits in socially isolated mice
    9. A novel promising therapy for anxiety disorders and PTSD
    10. Closing remarks
    Neurosteroid Biosynthesis Upregulation: A Novel Promising Therapy for Anxiety Disorders and PTSD

    1. Introduction

    Generalized anxiety, panic, and posttraumatic stress disorder (PTSD) are debilitating conditions, which have an incidence of one in ten persons in the general population and epidemiological studies also report that these disorders often occur with depression (1-3). Anxiolytic benzodiazepines, including diazepam and alprazolam, remain the best and most used treatments for these conditions (4-7). However, their therapeutic use is associated with side effects, which include sedation and rapid development of tolerance as well as dependence. This results in severe discontinuation symptoms and often to drug abuse (4-6, 8; 9).

    In many patients, including patients with PTSD, the pharmacological effects of these drugs are very weak and there is a large number of non-responders (10-12). This has stimulated drug design that for many decades has focused in the development of new more effective therapies for anxiety disorders (13-15). Novel neuronal biomarkers for the pharmacological targets of the next generation of anxiolytic drugs have been discovered.

    The downregulation of neurosteroid biosynthesis has been implicated in the pathophysiology of anxiety and depressive disorders (reviewed in 16). Decreases in cerebrospinal fluid (clinical studies) and brain content (preclinical studies) of the GABAA receptor-active progesterone derivative, allopregnanolone, have been associated with affective and mood disorders, which includes depression, anxiety spectrum disorders, PTSD, premenstrual dysphoric disorder, schizophrenia, and impulsivity (17-27). Thus, elevating or normalizing the downregulation of brain allopregnanolone levels could be a promising therapeutic strategy for these psychiatric disorders. This prompted investigations to develop new neurosteroidogenic agents to contrast allopregnanolone biosynthesis deficits in anxiety and depression (28-31).

    We measured allopregnanolone levels in the cerebrospinal fluid (CSF) of PTSD patients assuming that allopregnanolone levels in the CSF reflect the levels of this neurosteroid in the brain (17). Also, in depressed patients, the concentration of allopregnanolone in the CSF was decreased by about 50-60% of the levels measured in non-psychiatric patients (26). The CSF allopregnanolone level decrease is likely induced by a downregulation of the expression of 5α-reductase type I mRNA in the prefrontal-cortex (area BA9) that we measured in depressed patients and age- and sex-matched non-psychiatric subjects (32). The cortical level of 5α-reductase mRNA in depressed patients was dramatically decreased to about 50% of the levels measured in non-psychiatric comparison subjects, whereas the levels of 5α-reductase mRNA was unchanged in the cerebellum (32). In depressed patients, SSRI treatment with fluoxetine and fluvoxamine normalized the CSF allopregnanolone content (26) in a manner that correlated with the improvement in depressive symptoms. These results were confirmed in studies that determined allopregnanolone or levels of 5α-tetrahydrodeoxycorticosterone, another positive modulator of GABAA receptor function, in the plasma of depressed patients treated with SSRIs (33).

    In premenopausal women with PTSD, the CSF allopregnanolone levels were decreased by about 60% and were inversely correlated with PTSD re-experiencing and comorbid depressive symptoms (17). Interestingly, CSF allopregnanolone levels were lowest in those patients with PTSD and comorbid depression. Also, the ratio of allopregnanolone to its steroid precursor, 5α-dihydroprogesterone (5α-DHP), was decreased among the PTSD patients, suggesting the presence of an impairment in the biosynthesis of allopregnanolone from its precursor 5α-DHP (17). These data suggest that the downregulation of brain allopregnanolone levels in PTSD and depressed patients may cause a GABAergic neurotransmission dysfunction, which in turn results in the behavioral symptoms seen in these patients.

    Following the finding that fluoxetine and paroxetine and other SSRIs increase the content of allopregnanolone in several rodent brain structures (34), we hypothesized that normalization of brain allopregnanolone levels may underlie the pharmacological effects of the so called “selective serotonin reuptake inhibitors” or SSRIs in mood disorders. To test this hypothesis, we conducted experiments using the socially isolated mouse as an animal model of anxiety disorders and PTSD (16; 35-38). The socially isolated mouse expresses a robust decrease of corticolimbic allopregnanolone levels, which are associated with anxiety-like behaviors, fear, resistance to sedation, and heightened aggression (16; 35; 39). These behavioral deficits can be ameliorated by administration of fluoxetine and other SSRIs that upregulate allopregnanolone levels. Interestingly, fluoxetine’s pharmacological effects resulted to be independent from the ability of this drug to inhibit serotonin reuptake (35; 36).

    Our experiments support a selective and novel mechanism whereby SSRIs, acting as selective brain steroidogenic stimulants (SBSSs), increase brain corticolimbic allopregnanolone levels and improve PTSD, anxiety, and depression behavioral symptoms.

    2. Neurosteroids modulation of GABAA receptors function

    Biosynthesis of neurosteroids in the brain is independent from adrenals, ovaries, and testis (40-44). Neurosteroids are functionally active in modulating gene expression and neurotransmitter systems (45-52). Allopregnanolone exerts pharmacological actions, such as anticonvulsant, anxiolytic, antidepressant, and even sedative-hypnotic (53-60). These pharmacological actions are similar to those elicited by barbiturates and benzodiazepines (52; 61; 62). Allopregnanolone potently (nM affinity), positively, and allosterically modulates the action of GABA at GABAA receptors (45-51). The endogenous physiological relevance of allopregnanolone is substantiated by its facilitation and fine-tuning of the efficacy of direct GABAA receptor activators and positive allosteric modulators of GABA action at GABAA receptors (43; 47; 48; 63). The demonstration that allopregnanolone potentiates GABA responses via two binding sites in the GABAA receptor that, respectively, mediate the potentiation and the direct activation of the GABAA receptor by allopregnanolone has been pivotal in neurosteroid pharmacology (64). Also, GABAA receptors incorporating α4, α6, and δ subunits in combination with γ and β subunits show higher affinity (nM range) for allopregnanolone (45; 46; 51; 64; 65). Relevant for pharmacological strategies to overcome behavioral deficits resulting from GABAA receptor signal transduction deficits, allopregnanolone allosteric modulation of the action of GABA at GABAA receptors is much less selective than that of benzodiazepines, which are relatively inactive at α4- or α6-containing GABAA receptors (4; 45; 46; 66).

    3. Neurosteroid biosynthesis in corticolimbic neurons

    A study of the neuronal localization of the neurosteroidogenic enzymes, 5α-reductase type I and 3α-hydroxysteroid dehydrogenase (3α-HSD), has recently showed that these enzymes are not expressed in GABAergic cortical interneurons or glial cells (67). Of note, 5α-reductase and 3α-HSD were highly expressed and co-localized in a region-specific way in primary GABAergic and glutamatergic neurons, including pyramidal neurons, granular cells, reticulo-thalamic neurons, medium spiny neurons of the striatum and nucleus accumbens, and Purkinje cells in the cerebellum (67). This suggested that allopregnanolone synthesized in glutamatergic cortical or hippocampal pyramidal neurons or in granular cells of the dentate gyrus may be secreted in: 1) a paracrine manner which would allow allopregnanolone to reach GABAA receptors located in the synaptic membranes of other cortical or hippocampal pyramidal neurons, or 2) an autocrine fashion which would allow allopregnanolone to act locally by binding post-synaptic or extra-synaptic GABAA receptors located on the same dendrites or cell bodies of the cortical or hippocampal pyramidal neuron in which it was produced (67). Alternatively, allopregnanolone might not be released, but may instead diffuse laterally into synaptosome membranes of the cell bodies or dendritic arborization of glutamatergic neurons in which it is produced to attain intracellular access to specific neurosteroid binding sites of GABAA receptors (67; 68). In the amygdala, for example, this would functionally baffle the effects of concomitant excitatory inputs to glutamatergic projection neurons during exposure to unconditioned stress during fear conditioning or to conditioned stressors during extinction.

    On the other hand, allopregnanolone produced in primary output GABAergic neurons from the reticular thalamic nucleus may secrete allopregnanolone simultaneously with GABA to concomitantly act at post-synaptic GABAA receptors inserted in glutamatergic thalamocortical neurons (69). Very similarly, allopregnanolone synthesized by striatal medium spiny GABAergic neurons and cerebellar Purkinje cells may activate post-synaptic GABAA receptors located on cell bodies or dendrites of neurons in the deep cerebellar nuclei (67).

    The clarification of allopregnanolone site of synthesis and action across several brain regions has been pivotal to our understanding of the possible mechanisms by which allopregnanolone is secreted and acts at GABAA receptors. These studies underscore the functional role of allopregnanolone in fine tuning the strength of GABAergic neurotransmission under physiological conditions and how deficits in allopregnanolone biosynthesis may result in abnormal behavior.

    4. Social isolation induces a selective neuron-specific decrease of 5α-reductase in corticolimbic neurons

    Exposure of rodents to protracted social isolation stress for 4-8 weeks induces a decrease in allopregnanolone biosynthesis in several corticolimbic structures as a result of a downregulation of the mRNA and protein expression of 5α-reductase type I (35; 70-73; reviewed in 38). Socially isolated mice show a 70% reduction in the synthesis rate of allopregnanolone and 5α-DHP biosynthesis compared to group-housed mice (35; 72).

    Allopregnanolone and 5α-DHP are unevenly distributed and expressed in various brain structures (48; 74). The rodent olfactory bulb shows the highest concentrations of 5α-DHP and allopregnanolone followed by the frontal cortex, hippocampus, amygdala, striatum, and cerebellum (74). Interestingly, the largest decrease of 5α-reductase was found in brain regions regulating emotional behavior, including the amygdala and hippocampus, followed by the olfactory bulb and the frontal cortex (74). The expression of 5α-reductase failed to change in the cerebellum and striatum (74; 75). Decreased 5α-reductase was specifically found in cortical pyramidal neurons of layers V-VI, in hippocampal CA3 pyramidal neurons and glutamatergic granular cells of the dentate gyrus, and in the pyramidal-like neurons of the basolateral amygdala (75). However, 5α-reductase fails to change in GABAergic neurons of the reticular thalamic nucleus, central amygdala, cerebellum, and in the medium spiny neurons of the caudatus and putamen (75). In these brain areas, we confirmed that the decrease of 5α-reductase resulted in a reduction of allopregnanolone levels (74; 76; 77). Social isolation failed to change the expression of 3α-HSD, the mRNA expression of diazepam binding inhibitor, and the expression of the 18 kDa translocase protein (TSPO), which is involved in the transport of cholesterol across the inner mitochondrial membrane and activation of neurosteroidogenesis (reviewed in 72). Thus, the downregulation of 5α-reductase appears to be the main factor responsible for the reduction of corticolimbic allopregnanolone levels.

    5. GABAergic neurotransmission deficits resulting from allopregnanolone downregulation

    Allopregnanolone biosynthesis downregulation as a result of social isolation stress or pharmacological decrease of allopregnanolone induced by inhibiting 5α-reductase with the potent competitive 5α-reductase inhibitor SKF 105,111 decreases GABAergic neurotransmission as demonstrated by reduced loss of righting reflexes induced by GABAA receptor active ligands. The effects of SKF on the muscimol-, pentobarbital-, benzodiazepine-, or alcohol-induced loss of righting reflex loss can be reversed by the systemic or intracerebroventricular administration of allopregnanolone (43; 48). Likewise, social isolation or SKF-induced decrease of allopregnanolone results in facilitation of the seizure activity induced by several drugs that decrease GABAA receptor function, including picrotoxin (63). Administration of allopregnanolone at doses that have virtually no effects on group-housed control mice normalized the increased susceptibility to picrotoxin-induced seizures in SKF-treated or social isolated mice (63). The protracted social isolation or SKF treatment-induced allopregnanolone biosynthesis downregulation appeared to be the primary reason for the GABAA receptor signal transduction deficits observed in these mice. In fact, seizures induced by kainic acid or strychnine in socially isolated mice are similar to those induced by these agents in group housed mice.

    6. Behavioral effects induced by allopregnanolone downregulation in corticolimbic areas

    The decrease of allopregnanolone biosynthesis in socially isolated mice has been associated with several behavioral deficits that resemble behavioral abnormalities observed in patients with PTSD (16; 17; 30; 38). Hence, this mouse model can be used to study the behavioral responses elicited by treatment with neurosteroidogenic agents, the SBSSs. This new class of drugs includes the SSRI antidepressants that have been shown to elicit a potent neurosteroidogenic activity selectively at low doses as their principal action.

    Allopregnanolone has emerged as an important biomarker of emotional behavioral deficits (16; 35-38; 72). This was demonstrated by experiments using socially isolated mice to induce a downregulation of allopregnanolone biosynthesis. We have established a fundamental role for allopregnanolone in the regulation of anxiety-like and aggressive behavior as well as contextual fear conditioning, (16; 37; 63; 74; 77). When mice are socially isolated for a period varying from one to eight weeks, there is a time-dependent increase in aggressive behavior over the first four weeks of isolation, which is inversely correlated with a time-dependent decrease of corticolimbic allopregnanolone levels (35). Likewise, socially isolated mice exposed to a classical fear conditioning paradigm showed enhanced conditioned contextual but not cued fear responses compared with group housed mice (74). The time-related increase of contextual fear responses correlated with the downregulation of 5α-reductase mRNA and protein expression observed in the frontal cortex, hippocampus, and amygdala (74). Socially isolated mice also exhibited impaired and incomplete fear extinction (74). Of note, socially isolated mice also exhibit higher levels of anxiety-like behavior, determined by the elevated plus maze and in the open field (16; 39).

    Allopregnanolone plays a pivotal rather than incidental role in the regulation of contextual fear responses and aggression. In fact, pharmacological treatment with allopregnanolone dose-dependently decreased aggression in a manner that correlated with an increase in corticolimbic allopregnanolone content (35). Allopregnanolone also normalized the exaggerated contextual fear responses and anxiety of socially isolated mice (74). Further, administration of the potent 5α-reductase competitive inhibitor SKF 105,111 to normal group-housed mice (43; 48; 47) rapidly (~1 h) decreased levels of allopregnanolone in the olfactory bulb, frontal cortex, hippocampus, and amygdala by 80-90% (73; 74) in association with a dose-dependent increase of conditioned contextual fear responses (74). Administering allopregnanolone doses that normalized hippocampus allopregnanolone levels reversed
     
  2. jaguar43

    jaguar43 Member

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    this is great, ssri's dont even raise serotonin. I rembered he said that on an interview.
     
  3. Dorito Loyalist

    Dorito Loyalist Member

    Joined:
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    "It protects brain cells from injury caused by fatigue, and an adequate amount has a calming effect on the emotions, which is part of the reason that it protects us from the stress response that leads to an excessive production of cortisone. People feel a mood of resilience and an ability to confront challenges." - Ray Peat on Pregnenolone

    http://www.ssristories.com/index.php?p=school

    Is pregnenolone to blame for mass shootings?
     
  4. 4peatssake

    4peatssake Member

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    No
     
  5. HDD

    HDD Member

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    Can pregnenolone be taken while taking an SSRI? I thought someone had posted it should not, but I can't find the post.
     
  6. Swandattur

    Swandattur Member

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    My understanding was that SSRIs did raise levels of serotonin, but that that was not the mechanism of improving mood. They have a possible good effect and the bad effect of too much serotonin.
     
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