Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density

Fortuyn, H.A. Droogleever; Broekhoven, Frank van; Span, Paul N.; Bäckström, Torbjörn; Zitman, Frans G.; Verkes, Robbert J.

doi:10.1016/j.psyneuen.2004.02.003

Cited by 90 publications

(61 citation statements)

References 23 publications

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“…The subjects knew that they were about to receive a compound never given to humans before, and electrodes for oculography had been mounted and intravenous cannulas inserted prior to testing. It is known that allopregnanolone and most likely also isoallopregnanolone increase after stress both in humans and animals (Droogleever et al 2004;Purdy et al 1991). The allopregnanolone concentrations at baseline in our subjetcs are slightly lower than in amenorrheic patients known to have a high adrenal stimulation (Genazzani et al 2002).…”

Section: Discussioncontrasting

confidence: 51%

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

et al. 2008

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Rationale: The pharmacokinetics and behavioral effects of isoallopregnanolone (3β-hydoxy-5α-pregnan-20-one) in women are not known.Objectives: Allopregnanolone (3α-hydoxy-5α-pregnan-20-one) is a well known neurosteriod, acting via the GABA A receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3β-stereoisomer of allopregnanolone. Prior studies have concluded that isoallopregnanolone has no effect on the GABA A receptor. However, an antagonistic effect of isoallopregnanolone to allopregnanolone on the GABA A receptor has been shown in animal and in vitro studies. The purpose of this study was to evaluate the pharmacokinetics and behavioral effects of isoallopregnanolone in humans.Methods: Six healthy women were given three increasing doses of isoallopregnanolone intravenously in the follicular phase. Repeated blood samples for analyses of isoallopregnanolone and allopregnanolone concentrations were drawn. Saccadic eye movement variables, self rated sedation and mood rating scales were used during the test day.A Likert scale for prospective symptoms was used to measure daily fluctuations during the ongoing menstrual cycle.Results: Exogenously administered isoallopregnanolone produced a dose dependent increase in the serum concentration of isoallopregnanolone. In parallel there was also a rise in the allopregnanolone concentration. There was a decrease in saccade eye movement variables, but no effect was found on self-rated sedation or mood and no changes were seen in prospective symptoms during the menstrual cycle.Conclusions: After administration of isoallopregnanolone at a cumulative dose of 0.20 mg/kg, no adverse effects were observed. There is a metabolism of isoallopregnanolone to allopregnanolone, most likely explaining the effects on the saccadic eye movements.3

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Section: Discussioncontrasting

confidence: 51%

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

et al. 2008

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“…Although estrogen and progesterone have been shown in some studies to enhance and diminish HPA axis activation (Fonseca et al, 2001;Patchev et al, 1994), respectively, ALLO concentrations in plasma and brain increase as a result of stress (Barbaccia et al, 1997(Barbaccia et al, , 2001), perhaps as a compensatory mechanism. Women with PMDD fail to demonstrate the normal increase in ALLO seen in healthy subjects under conditions of stress (Monteleone et al, 2000;Girdler et al, 2001;Droogleever Fortuyn et al, 2004;Lombardi et al, 2004), or during HPA axis activation with ACTH administration (Genazzani et al, 1998;Lombardi et al, 2004). In the context of this study, the acoustic startle procedure can be viewed as mildly stress inducing.…”

Section: Discussionmentioning

confidence: 94%

Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder

Epperson

Pittman

Czarkowski

et al. 2007

Neuropsychopharmacol

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Alterations in central nervous system response to menstrual cycle-related fluctuations in neuroactive steroids are thought to underlie the emergence of negative affect in the luteal phase of the menstrual cycle in women with premenstrual dysphoric disorder (PMDD). Such changes in the neuroendocrine milieu may lead to heightened arousal and response to stress in women with PMDD. Using the acoustic startle paradigm, we sought to determine whether women with PMDD have an accentuated physiologic response to a mildly aversive stimulus during the luteal compared to follicular phase. Further, we also examined the impact of visual affective stimuli on acoustic startle response (ASR) magnitude. During the follicular and luteal phases of the menstrual cycle, acoustic stimuli (103 dB) were delivered to 15 women with PMDD and 14 healthy menstruating women of similar age. After obtaining baseline ASR, the procedure was repeated when subjects viewed pleasant, neutral and unpleasant pictures. There was a significant group by menstrual cycle phase interaction for baseline ASR magnitude, which can be attributed to the heightened startle magnitude in women with PMDD compared to healthy women during the luteal relative to the follicular phase. The direction and degree to which picture viewing modulated the startle magnitude did not vary by group or menstrual cycle phase. These data suggest that menstrual cycle phase has a powerful modulatory effect on physiologic reactivity in women with PMDD but not in healthy women. Physiologic response to affective stimuli appears to be intact in women with PMDD across the menstrual cycle.

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“…Social isolation stress has also been shown to increase neurosteroid formation in male rodents (Dong et al, 2001). In humans, examination stress (Droogleever Fortuyn et al, 2004) and performance stress (Girdler et al, 2006) were also accompanied by significant elevations in circulating levels of THP in both sexes, although ethnic differences have been reported (Girdler et al, 2006). Recent studies also suggest that drugs such as alcohol (VanDoren et al, 2000), morphine and δ-9-tetrahydrocannabinol (Grobin et al, 2005) increase circulating THP levels as a long-term response to intake of these drugs.…”

Section: Stress and Addictive Drugsmentioning

confidence: 99%

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

Smith

Shen

Gong

et al. 2007

Pharmacology & Therapeutics

214

197

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Neurosteroids, such as the progesterone metabolite 3α-OH-5α[β]-pregnan-20-one (THP or [allo] pregnanolone), function as potent positive modulators of the GABA A receptor (GABAR) when acutely administered. However, fluctuations in the circulating levels of this steroid at puberty, across endogenous ovarian cycles, during pregnancy or following chronic stress produce periods of prolonged exposure and withdrawal, where changes in GABAR subunit composition may occur as compensatory responses to sustained levels of inhibition. A number of laboratories have demonstrated that both chronic administration of THP as well as its withdrawal transiently increase expression of the α4 subunit of the GABAR in several areas of the central nervous system (CNS) as well as in in vitro neuronal systems. Receptors containing this subunit are insensitive to benzodiazepine (BDZ) modulation and display faster deactivation kinetics, which studies suggest underlie hyperexcitability states. Similar increases in α4 expression are triggered by withdrawal from other GABA-modulatory compounds, such as ethanol and BDZ, suggesting a common mechanism. Other studies have reported puberty or estrous cycle-associated increases in δ-GABAR, the most sensitive target of these steroids which underlies a tonic inhibitory current. In the studies reported here, the effect of steroids on inhibition, which influence anxiety state and seizure susceptibility, depend not only on the subunit composition of the receptor but also on the direction of Cl -current generated by these target receptors. The effect of neurosteroids on GABAR function thus results in behavioral outcomes relevant for pubertal mood swings, premenstrual dysphoric disorder and catamenial epilepsy, which are due to fluctuations in endogenous steroids.

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Effects of PhD examination stress on allopregnanolone and cortisol plasma levels and peripheral benzodiazepine receptor density

Cited by 90 publications

References 23 publications

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

Luteal-Phase Accentuation of Acoustic Startle Response in Women with Premenstrual Dysphoric Disorder

Neurosteroid regulation of GABAA receptors: Focus on the α4 and δ subunits

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