Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons

Bäckström, Torbjörn; Haage, David; Löfgren, Mats; Johansson, Ingvar; Strömberg, Jessica; Nyberg, Sigrid; Andréen, Lotta; Ossewaarde, Lindsey; Wingen, Guido van; Türkmen, Şahruh; Bengtsson, Sara K.

doi:10.1016/j.neuroscience.2011.03.061

Cited by 148 publications

(96 citation statements)

References 105 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However the same effects on behavior were not present in asymptomatic controls with no past history of PMDD who underwent the identical protocol. These data suggest that women with PMDD have a differential sensitivity to changes in allopregnanolone levels, perhaps at the level of the GABA A R (Backström et al, 2011) (possibly reflecting an increased expression of the α4βδ GABA-A receptor in PMDD that could result in allopregnanolonemediated decreased inhibition and anxiety-like behaviors (Shen et al, 2007)), or secondary to an altered metabolism of allopregnanolone and other neurosteroids within the CNS. The role of progesterone and its 5α-reduced metabolites in affective regulation is supported by several findings in humans (Schiller et al, 2014).…”

Section: Discussionmentioning

confidence: 93%

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

121

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 93%

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

121

View full text Add to dashboard Cite

show abstract

“…Endogenous neurosteroids are powerful mood and motivation modulators in animals and humans (Backstrom et al, 2011;Lambert et al, 2009;Zorumski et al, 2013). Neurosteroids may also strongly influence responses to drugs of abuse.…”

Section: Introductionmentioning

confidence: 99%

Neurosteroid Agonist at GABAA Receptor Induces Persistent Neuroplasticity in VTA Dopamine Neurons

Vashchinkina

Manner

Vekovischeva

et al. 2013

Neuropsychopharmacol

View full text Add to dashboard Cite

The main fast-acting inhibitory receptors in the mammalian brain are g-aminobutyric acid type-A (GABA A ) receptors for which neurosteroids, a subclass of steroids synthesized de novo in the brain, constitute a group of endogenous ligands with the most potent positive modulatory actions known. Neurosteroids can act on all subtypes of GABA A receptors, with a preference for d-subunitcontaining receptors that mediate extrasynaptic tonic inhibition. Pathological conditions characterized by emotional and motivational disturbances are often associated with perturbation in the levels of endogenous neurosteroids. We studied the effects of ganaxolone (GAN)-a synthetic analog of endogenous allopregnanolone that lacks activity on nuclear steroid receptors-on the mesolimbic dopamine (DA) system involved in emotions and motivation. A single dose of GAN in young mice induced a dose-dependent, longlasting neuroplasticity of glutamate synapses of DA neurons ex vivo in the ventral tegmental area (VTA). Increased a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/N-methyl-D-aspartate ratio and rectification of AMPA receptor responses even at 6 days after GAN administration suggested persistent synaptic targeting of GluA2-lacking AMPA receptors. This glutamate neuroplasticity was not observed in GABA A receptor d-subunit-knockout (d-KO) mice. GAN (500 nM) applied locally to VTA selectively increased tonic inhibition of GABA interneurons and triggered potentiation of DA neurons within 4 h in vitro. Place-conditioning experiments in adult wild-type C57BL/6J and d-KO mice revealed aversive properties of repeated GAN administration that were dependent on the d-subunits. Prolonged neuroadaptation to neurosteroids in the VTA might contribute to both the physiology and pathophysiology underlying processes and changes in motivation, mood, cognition, and drug addiction.

show abstract

“…However, compared to controls, an increase in symptom severity has been associated with decreased concentrations of allopregnanolone in women with PMDD [48]. A depression of progesterone, allopregnanolone and estradiol to low follicular phase levels using a low-dose COC with levonorgestrel 100 mcg/EE 20 mcg did not induce mood symptoms in women with no history of affective disorder [44]. For women with PMS/PMDD, more research is needed.…”

Section: Studies Showing Improving Effects Of Cocsmentioning

confidence: 94%

“…Allopregnanolone, a neuroactive steroid and a metabolite of progesterone, seems to be important for the development of symptoms in PMS/PMDD [44]. Neuroactive steroids and precursors to neuroactive steroids like progesterone and estrogen are decreased in women taking COCs with allopregnanolone levels during the premenstrual phase comparable to or lower than levels seen during the follicular phase in women with normal cycles [45].…”

Section: Studies Showing Improving Effects Of Cocsmentioning

confidence: 99%

Mood and physical symptoms improve in women with severe cyclical changes by taking an oral contraceptive containing 250-mcg norgestimate and 35-mcg ethinyl estradiol

Nyberg

2013

Contraception

View full text Add to dashboard Cite

Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons

Cited by 148 publications

References 105 publications

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

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

Neurosteroid Agonist at GABAA Receptor Induces Persistent Neuroplasticity in VTA Dopamine Neurons

Mood and physical symptoms improve in women with severe cyclical changes by taking an oral contraceptive containing 250-mcg norgestimate and 35-mcg ethinyl estradiol

Contact Info

Product

Resources

About