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Allopregnanolone has no effect on startle response and prepulse inhibition of startle response in patients with premenstrual dysphoric disorder or healthy controls
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktiv hälsa/Sundström Poromaa)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Reproduktiv hälsa/Sundström Poromaa)
2009 (English)In: Pharmacology, Biochemistry and Behavior, ISSN 0091-3057, E-ISSN 1873-5177, Vol. 92, no 4, 608-613 p.Article in journal (Refereed) Published
Abstract [en]

Background: Allopregnanolone is an endogenous neuroactive steroid  which, through the binding to the GABA(A) receptor. enhances inhibitory   neurotransmission and exerts anxiolytic, sedative and antiepileptic  effects. Following acute administration, allopregnanolone reliably acts as an anxiolytic compound. The primary aim of this study was to investigate if allopregnanolone, administered to healthy women and   women with premenstrual dysphoric disorder (PMDD), would have an anxiolytic effect, expressed as a decreased startle response.   Materials and methods: Sixteen PMDD patients and twelve healthy   controls completed the study. The participants were scheduled for the   startle tests twice in the luteal phase. During the test sessions an intravenous allopregnanolone and placebo bolus injection was administered in double-blinded, randomized order at intervals of 48 h. Following the allopregnanolone/placebo injections startle response and   prepulse inhibition of startle response (PPI) were assessed by   electromyography.   Results: Following the intravenous allopregnanolone administration the   serum concentrations of allopregnanolone increased to 50-70 nmol/l.   corresponding to levels that are seen during pregnancy. The obtained   serum concentrations of allopregnanolone were significantly lower in   PMDD patients than among the healthy controls, p<0.05. The   allopregnanolone injection resulted in significant increases of   self-rated sedation in both groups, p<0.01. Allopregnanolone did not induce any changes in startle response or prepulse inhibition of   startle response in comparison to placebo. No differences in allopregnanolone-induced changes in startle response or PPI could be detected between PMDD patients and controls subjects. Conclusion: Startle response and PPI were unaffected by acute   intravenous administration of allopregnanolone in PMDD patients and healthy controls.

Place, publisher, year, edition, pages
2009. Vol. 92, no 4, 608-613 p.
Keyword [en]
Allopregnanolone, Premenstrual dysphoric disorder, Startle response, Prepulse inhibition
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97755DOI: 10.1016/j.pbb.2009.02.014ISI: 000266538800008PubMedID: 19268499OAI: oai:DiVA.org:uu-97755DiVA: diva2:172813
Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2010-07-26Bibliographically approved
In thesis
1. Hormones, Mood and Cognition
Open this publication in new window or tab >>Hormones, Mood and Cognition
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Ovarian steroid hormones are neuroactive steroids with widespread actions in the brain, and are thus able to influence mood, behavior and cognition.

In this thesis the effects of progesterone withdrawal and the direct effects of the progesterone metabolite allopregnanolone are evaluated.

Allopregnanolone, through binding to the GABAA receptor complex, enhances inhibitory neurotransmission, thus exerting anxiolytic, sedative and antiepileptic effects.

The acoustic startle response (ASR) is a withdrawal reflex evoked by sudden or noxious auditory stimuli, and can be measured in humans as an eye blink. ASR is significantly increased in several anxiety disorders, and notably also during progesterone withdrawal.

Sensorimotor gating can be assessed by measuring prepulse inhibition of the startle response (PPI). The CNS circuits regulating PPI are sensitive to hormone fluctuations. GABAergic drugs are involved in cognitive impairment and animal studies have indicated that allopregnanolone may inhibit learning.

The main purpose of this research was to evaluate the behavioral effects of progesterone withdrawal on the startle response and sensorimotor gating in PMDD patients and healthy controls, in healthy third trimester pregnant women and healthy postpartum women. A second aim was to evaluate allopregnanolone effects on memory and cognition in healthy women and also on the startle response and PPI.

We found that PMDD patients have an increased startle response across the menstrual cycle and a deficiency in sensorimotor gating during the late luteal phase.

Ovarian steroids affect sensorimotor gating; pregnant women have lower levels of PPI than late postpartum women. Acutely administered allopregnanolone did not affect the ASR or PPI. Allopregnanolone impairs episodic memory in healthy women.

In conclusion, our studies suggest that ovarian steroids, including allopregnanolone, do not influence the startle response. Ovarian steroids affect sensorimotor gating; pregnancy, a condition with high levels of ovarian steroids, suppresses PPI. Theoretically, the variability in PPI across reproductive events is due to effects mediated by the progesterone or estradiol receptors but is not mediated by allopregnanolone. PMDD patients display decreased PPI during the late luteal phase, suggesting underlying pathophysiology in common with other anxiety disorders. The most vulnerable memory system, the episodic memory, is impaired by the allopregnanolone in healthy women.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 91 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 394
startle response; prepulse inhibition; premenstrual dysphoric disorder; menstrual cycle; pregnancy; postpartum period; episodic memory; semantic memory; working memory; progesterone; estradiol; allopregnanolone.
National Category
Clinical Science
urn:nbn:se:uu:diva-9365 (URN)978-91-554-7332-7 (ISBN)
Public defence
2008-12-05, Rosénsalen, Uppsala University Hospital, Entrance 95/96, Uppsala, 13:15
Available from: 2008-11-14 Created: 2008-11-14Bibliographically approved

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