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      Prenatal resident-intruder stress decreases levels of allopregnanolone in the cortex, hypothalamus, and midbrain of males, and increases levels in the hippocampus and cerebellum of female, juvenile rat offspring

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          Abstract

          Prenatal stress (PNS) can influence behaviors associated with cognition, reward and emotional regulation, which are controlled by brain areas such as the cortex, hippocampus, hypothalamus, midbrain and cerebellum. Allopregnanolone in these regions modulates behavioral and parasympathetic effects. The current study tested whether exposing pregnant dams to 5 days of resident-intruder stress on prenatal days 15–20 for 10 min altered the levels of allopregnanolone in cortex, hypothalamus, hippocampus, midbrain, and cerebellum of male and female juvenile offspring. In cortex, hypothalamus, and midbrain of male rats exposed to prenatal stress, levels of allopregnanolone were significantly lower compared to all other groups. In the hippocampus and cerebellum, among females exposed to prenatal stress levels were significantly higher compared to all other groups. These differences in allopregnanolone levels varying by prenatal stress, sex and brain regions provide insight in potential mechanism of stress regulation and etiopathophysiology of stress-related disorders.

          Highlights

          • In cortex, hypothalamus and midbrain, prenatal stress decreased allopregnanolone in males compared to all other groups.

          • In hippocampus and cerebellum, prenatal stress females had higher levels of allopregnanolone compared to all other groups.

          • Allopregnanolone levels caused by resident intruder stress were similar to levels seen in prenatal stress due to other means.

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          Most cited references39

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          Effects of antidepressant treatment on neuroactive steroids in major depression.

          There is evidence from animal studies that fluoxetine may enhance the concentrations of neuroactive steroids. Therefore, the authors investigated whether clinically effective treatment with antidepressants may alter the concentrations of neuroactive steroids in patients suffering from a major depressive episode. In the first study, eight drug-naive outpatients with major depression were studied during treatment with fluoxetine. In a complementary study, 11 inpatients with major depression were studied during a severe depressive episode and after recovery following treatment with different antidepressants. Plasma samples were quantified for neuroactive steroids by means of a highly sensitive and specific combined gas chromatography/mass spectrometry analysis. During depression, there was a significant decrease in 3 alpha, 5 alpha-tetrahydroprogesterone (3 alpha, 5 alpha-THP) and 3 alpha, 5 beta-THP concentrations, both of which are positive modulators of the gamma-aminobutyric acidA receptor, and a concomitant increase in 3 beta, 5 alpha-THP levels. This dysequilibrium of neuroactive steroids could be corrected by treatment with different antidepressants. These results provide the first clinical evidence of a possible role of neuroactive steroids in successful antidepressant therapy.
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            Prenatal social stress in the rat programmes neuroendocrine and behavioural responses to stress in the adult offspring: sex-specific effects.

            Stress exposure during pregnancy can 'programme' adult behaviour and hypothalamic-pituitary-adrenal (HPA) axis stress responsiveness. In the present study, we utilised an ethologically relevant social stressor to model the type of stress that pregnant women may experience. We investigated the effects of social defeat by a resident lactating rat over 5 days during the last week of pregnancy on the pregnant intruder rat HPA axis, and on HPA responsivity to stress and anxiety-related behaviour in the adult offspring of the socially-defeated intruder rats. HPA axis responses after social defeat were attenuated in the pregnant rats compared to virgin females. In the adult offspring, systemic interleukin (IL)-1beta or restraint increased adrenocorticotrophic hormone and corticosterone secretion in male and female control rats; however, in prenatally stressed (PNS) offspring, HPA responses were greatly enhanced and peak hormone responses to IL-1beta were greater in females versus males. Male PNS rats displayed increased anxiety behaviour on the elevated plus maze; however, despite marked changes in anxiety behaviour across the oestrous cycle, there were no differences between female control and PNS rats. Investigation of possible mechanisms showed mineralocorticoid mRNA levels were reduced in the hippocampus of male and female PNS offspring, whereas glucocorticoid receptor mRNA expression was modestly reduced in the CA2 hippocampal subfield in female PNS rats only. Corticotropin-releasing hormone mRNA and glucocorticoid receptor mRNA expression in the central amygdala was greater in PNS males and females compared to controls. The data obtained in the present study indicate that prenatal social stress differentially programmes anxiety behaviour and HPA axis responses to stress in male and female offspring. Attenuated glucocorticoid feedback mechanisms in the limbic system may underlie HPA axis hyper-reactivity to stress in PNS offspring.
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              Selective serotonin reuptake inhibitors directly alter activity of neurosteroidogenic enzymes.

              The neurosteroid 3alpha-hydroxysteroid-5alpha-pregnan-20-one (allopregnanolone) acts as a positive allosteric modulator of gamma-aminobutyric acid at gamma-aminobutyric acid type A receptors and hence is a powerful anxiolytic, anticonvulsant, and anesthetic agent. Allopregnanolone is synthesized from progesterone by reduction to 5alpha-dihydroprogesterone, mediated by 5alpha-reductase, and by reduction to allopregnanolone, mediated by 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD). Previous reports suggested that some selective serotonin reuptake inhibitors (SSRIs) could alter concentrations of allopregnanolone in human cerebral spinal fluid and in rat brain sections. We determined whether SSRIs directly altered the activities of either 5alpha-reductase or 3alpha-HSD, using an in vitro system containing purified recombinant proteins. Although rats appear to express a single 3alpha-HSD isoform, the human brain contains several isoforms of this enzyme, including a new isoform we cloned from human fetal brains. Our results indicate that the SSRIs fluoxetine, sertraline, and paroxetine decrease the K(m) of the conversion of 5alpha-dihydroprogesterone to allopregnanolone by human 3alpha-HSD type III 10- to 30-fold. Only sertraline inhibited the reverse oxidative reaction. SSRIs also affected conversions of androgens to 3alpha- and 3alpha, 17beta-reduced or -oxidized androgens mediated by 3alpha-HSD type II(Brain). Another antidepressant, imipramine, was without any effect on allopregnanolone or androstanediol production. The region-specific expression of 3alpha-HSD type II(Brain) and 3alpha-HSD type III mRNAs suggest that SSRIs will affect neurosteroid production in a region-specific manner. Our results may thus help explain the rapid alleviation of the anxiety and dysphoria associated with late luteal phase dysphoria disorder and major unipolar depression by these SSRIs.
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                Author and article information

                Contributors
                Journal
                Neurobiol Stress
                Neurobiol Stress
                Neurobiology of Stress
                Elsevier
                2352-2895
                03 March 2020
                May 2020
                03 March 2020
                : 12
                : 100214
                Affiliations
                [1]University at Albany – State University of New York, Comprehensive Neuropsychological Services, Albany, NY, 12203, USA
                Author notes
                []Corresponding author. Comprehensive Neuropsychological Services, 490 Western Avenue, Albany, NY, 12203, USA. cafrye@ 123456albany.edu
                Article
                S2352-2895(20)30004-7 100214
                10.1016/j.ynstr.2020.100214
                7109511
                0ec1d780-03b9-4191-825e-44a3450ae9f6
                © 2020 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 27 November 2019
                : 22 February 2020
                : 29 February 2020
                Categories
                Articles from the Special Issue on Allopregnanolone role in the neurobiology of stress and mood disorders; Edited by Graziano Pinna

                chronic stress,corticosterone,dopamine,microdialysis,spatial memory,rat

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