Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the female rat

Gulinello, Maria; Gong, Qiong; Li, X; Smith, Sheryl S.

doi:10.1016/s0006-8993(01)02565-3

Cited by 225 publications

(197 citation statements)

References 52 publications

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“…These hypotheses are supported by data from animal experiments in which low physiological doses of progesterone metabolites cause aggressive and aversive behavior but high dosages are inert or anxiolytic (23,24). In addition, during short-term treatment with physiologically relevant doses of progesterone in rats, a connection exists between progesterone-induced anxiety and upregulation of the a 4 subunit of the GABA A receptor in the hippocampus (25). In high dosages, progesterone will cause sedation and even anesthesia in both humans and other animals (8,15).…”

Section: Discussionmentioning

confidence: 87%

Progesterone effects during sequential hormone replacement therapy

Andréen

Bixo

Nyberg

et al. 2003

European Journal of Endocrinology

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Objective: The aim was to investigate the effect on mood and the physical symptoms of two dosages of natural progesterone and a placebo in postmenopausal women with and without a history of premenstrual syndrome (PMS). Design: A randomized, placebo-controlled, double-blind, crossover study was performed. Method: Postmenopausal women ðn ¼ 36Þ with climacteric symptoms were recruited. They received 2 mg estradiol continuously during three 28-day cycles. Vaginal progesterone suppositories with 800 mg/day, 400 mg/day, or placebo were added sequentially for 14 days per cycle. Daily symptom ratings using a validated rating scale were kept. Results: Women without a history of PMS showed cyclicity in both negative mood and physical symptoms while on 400 mg/day progesterone but not on the higher dose or the placebo. Women without a history of PMS had more physical symptoms on progesterone treatment compared with placebo. Women with prior PMS reported no progesterone-induced symptom cyclicity. Conclusion: In women without prior PMS natural progesterone caused negative mood effects similar to those induced by synthetic progestogens.

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Section: Discussionmentioning

confidence: 87%

Progesterone effects during sequential hormone replacement therapy

Andréen

Bixo

Nyberg

et al. 2003

European Journal of Endocrinology

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“…Incorporation of the d-subunit dramatically augments the GABA-enhancing actions of the steroid (Belelli et al, 2002;Mihalek et al, 1999Mihalek et al, , 2001. Therefore, the elevated levels of mRNA for the GABA A d-subunit in the VTA of FSL rats might be due to an intrinsic GABA-ergic intraneuron modulation (compensation) for low levels of DHEA in this brain region (Concas et al, 1999;Gulinello et al, 2001;Holt et al, 1996;Mahmoudi et al, 1997). The contrasting lower levels of mRNA for the d-subunit in the NAc of FSL compared to SD rats can be explained by different localization of GABA modulation on ascending neurons (Akiyama et al, 2004;Bankson and Yamamoto, 2004;Tao and Auerbach, 2002;Yan et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

Genud

Merenlender

Gispan-Herman

et al. 2008

Neuropsychopharmacol

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Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate g-aminobutyric-acid-type-A (GABA A R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (s1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitiveline (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the d-subunit of GABA A , but not of s1R mRNA, in FSL rats compared to SD rats. The d-subunit controls the sensitivity of the GABA A R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA A agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA A ), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA A Rs in the NAc and VTA.

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“…Preclinical studies indicate that the impact of neurosteroids on the GABA receptor is mediated by changes in their levels rather than their absolute concentration. Both increases and decreases in progesterone metabolite neurosteroids induce changes in the alpha 4 subunit conformation of the GABA A R sufficient to produce anxiety-like behaviors (Gulinello et al, 2001;Gulinello and Smith, 2003;Shen et al, 2005). Thus, it is possible that effects of progesterone to precipitate PMDD symptoms (Schmidt et al, 1998) could be mediated by changes in allopregnanolone and/or an abnormal conversion of progesterone to its neurosteroid metabolites.…”

Section: Introductionmentioning

confidence: 99%

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

Martinez¹,

Rubinow

Nieman

et al. 2015

Neuropsychopharmacol

118

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Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion of progesterone to its neurosteroid metabolite allopregnanolone in women with premenstrual dysphoric disorder (PMDD) and in asymptomatic control women. Sixteen women with prospectively confirmed PMDD and 16 control women participated in one of two separate randomized, doubleblind, placebo-controlled, cross-over trials, each lasting three menstrual cycles. After one menstrual cycle of single-blind placebo, participants were randomized to receive, for the next two menstrual cycles, either double-blind placebo or dutasteride (low-dose 0.5 mg/ day in the first eight PMDD and eight control women or high-dose 2.5 mg/day in the second group of women). All women completed the daily rating form (DRF) and were evaluated in clinic during the follicular and luteal phases of each menstrual cycle. Main outcome measures were the DRF symptoms of irritability, sadness, and anxiety. Analyses were performed with SAS PROC MIXED. In the low-dose group, no significant effect of dutasteride on PMDD symptoms was observed compared with placebo (ie, symptom cyclicity maintained), and plasma allopregnanolone levels increased in women with PMDD from follicular to the luteal phases, suggesting the absence of effect of the lowdose dutasteride on 5α-reductase. In contrast, the high-dose group experienced a statistically significant reduction in several core PMDD symptoms (ie, irritability, sadness, anxiety, food cravings, and bloating) on dutasteride compared with placebo. Dutasteride had no effect on mood in controls. Stabilization of allopregnanolone levels from the follicular to the luteal phase of the menstrual cycle by blocking the conversion of progesterone to its 5α-reduced neurosteroid metabolite mitigates symptoms in PMDD. These data provide preliminary support for the pathophysiologic relevance of neurosteroids in this condition.

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Short-term exposure to a neuroactive steroid increases α4 GABAA receptor subunit levels in association with increased anxiety in the female rat

Cited by 225 publications

References 52 publications

Progesterone effects during sequential hormone replacement therapy

Progesterone effects during sequential hormone replacement therapy

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

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