Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons
Abstract
Some women have negative mood symptoms, caused by progestagens in hormonal contraceptives or sequential hormone therapy or by progesterone in the luteal phase of the menstrual cycle, which may be attributed to metabolites acting on the GABA-A receptor. The GABA system is the major inhibitory system in the adult CNS and most positive modulators of the GABA-A receptor (benzodiazepines, barbiturates, alcohol, GABA steroids), induce inhibitory (e.g. anesthetic, sedative, anticonvulsant, anxiolytic) effects. However, some individuals have adverse effects (seizures, increased pain, anxiety, irritability, aggression) upon exposure. Positive GABA-A receptor modulators induce strong paradoxical effects including negative mood in 3%-8% of those exposed, while up to 25% have moderate symptoms. The effect is biphasic: low concentrations induce an adverse anxiogenic effect while higher concentrations decrease this effect and show inhibitory, calming properties. The prevalence of premenstrual dysphoric disorder (PMDD) is also 3%-8% among women in fertile ages, and up to 25% have more moderate symptoms of premenstrual syndrome (PMS). Patients with PMDD have severe luteal phase-related symptoms and show changes in GABA-A receptor sensitivity and GABA concentrations. Findings suggest that negative mood symptoms in women with PMDD are caused by the paradoxical effect of allopregnanolone mediated via the GABA-A receptor, which may be explained by one or more of three hypotheses regarding the pa…
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This finding may be consistent with previous evidence that menstrual-associated symptoms are more closely related to altered central nervous system sensitivity to hormonal fluctuations than to absolute hormone concentrations.
“This finding may be consistent with previous evidence suggesting that menstrual‐associated symptoms are more closely related to altered central nervous system sensitivity to hormonal fluctuations than to absolute hormone concentrations 20 , 21 , 22 , 23 , 24 .”
Menstrual-associated symptoms are more closely related to altered central nervous system sensitivity to hormonal fluctuations than to absolute hormone concentrations.
“This finding may be consistent with previous evidence suggesting that menstrual‐associated symptoms are more closely related to altered central nervous system sensitivity to hormonal fluctuations than to absolute hormone concentrations 20 , 21 , 22 , 23 , 24 .”
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- Authors
- Bäckström, T., Haage, D., Löfgren, M., Johansson, I. M., Strömberg, J., Nyberg, S., Andréen, L., Ossewaarde, L., van Wingen, G. A., Turkmen, S., & Bengtsson, S. K.
- Affiliations
- Umeå University (SE)
- Radboud University Nijmegen (NL)
- Corresponding author
- Bäckström, T.
- Venue
- Neuroscience
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 191
- Pages
- 46-54
- ISSN
- 0306-4522 (ISSN-L)
- OpenAlex
- W2132726881
- Cited by
- 169
- References
- 3
- Citations by year
- 2026: 2 · 2025: 11 · 2024: 12 · 2023: 18 · 2022: 17 · 2021: 10 · 2020: 13 · 2019: 12 · 2018: 5 · 2017: 10 · 2016: 8 · 2015: 14 · 2014: 11 · 2013: 13 · 2012: 9
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- GABA-A receptor modulators, paradoxical effects, sex steroids, premenstrual dysphoric disorder, premenstrual syndrome, allopregnanolone, progesterone, luteal phase, hormonal contraception, sequential hormone therapy, neurosteroids, estrogen, chloride gradient, neuronal excitability, biphasic effect
- MeSH terms
- Animals, Chlorides, Female, Humans, Menstrual Cycle, Neurons, Premenstrual Syndrome, Receptors, GABA-A, Steroids, GABA Modulators
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