Isoallopregnanolone antagonize allopregnanolone-induced effects on saccadic eye velocity and self-reported sedation in humans.

Allopregnanolone (AP) is an endogenous neurosteroid. It modulates the effect of γ-amino-butyric acid (GABA) on the GABA type A (GABAA) receptor, which leads to increased receptor activity. Since the GABA-system is mainly inhibitory, increased AP activity leads to modulation of neuronal activity. In vitro studies of GABAA receptor activity and in vivo animal studies of sedation have shown that AP-induced effects can be inhibited by another endogenous steroid, namely isoallopregnanolone (ISO). In this study we investigated if ISO can antagonize AP-induced effects in healthy female volunteers, via measurements of saccadic eye velocity (SEV) and self-rated sedation. With a single-blind cross-over design, 12 women were studied on three separate occasions; given AP alone or AP in combination with one of two ISO doses. Congruent with previous reports, AP administration decreased SEV and induced sedation and these effects were diminished by simultaneous ISO administration. Also, the ISO effect modulation was seemingly stronger for SEV than for sedation. These effects were observed already at an ISO dose exposure that was approximately half of that of AP. In conclusion, ISO antagonized AP-induced decrease in SEV and self-reported sedation, probably in a non-competitive manner.

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women.

RATIONALE: The pharmacokinetics and behavioral effects of isoallopregnanolone (3beta-hydoxy-5alpha-pregnan-20-one) in women are not known. OBJECTIVES: Allopregnanolone (3alpha-hydoxy-5alpha-pregnan-20-one) is a well-known neurosteroid, acting via the GABA(A) receptor in the human brain. The naturally occurring progesterone metabolite isoallopregnanolone is the 3beta-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. MATERIALS AND 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 saccadic 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.

Allopregnanolone decrease with symptom improvement during placebo and gonadotropin-releasing hormone agonist treatment in women with severe premenstrual syndrome.

BACKGROUND: Neurosteroids such as allopregnanolone and pregnanolone are suggested to be of importance for the pathophysiology of premenstrual dysphoric disorder. The aim of this study was to investigate whether the luteal-phase serum concentrations of these neurosteroids are associated with improvement of premenstrual symptoms in 12 women with severe premenstrual syndrome after treatment with low-dose gonadotropin-releasing hormone agonist and placebo. METHODS: Daily ratings for mood and physical symptoms were made prior to treatment and throughout the study. Serum progesterone, allopregnanolone and pregnanolone were assessed in the luteal phase (cycle day -9 to cycle day -1). Based on their symptom ratings, subjects were grouped as either buserelin responders (n = 6) or placebo responders (n = 6). RESULTS: Buserelin responders displayed decreased levels of allopregnanolone (p < 0.05) and progesterone (p < 0.05) in parallel with improvement of symptoms. During the placebo treatment, the placebo responders had lower serum allopregnanolone concentrations than buserelin responders (p < 0.05). This was associated with improvement in symptoms compared with pre-treatment ratings. CONCLUSION: Treatment response, whether induced by buserelin or placebo, appears to be associated with a decrease in allopregnanolone concentration.

The effect of a low dose of alcohol on allopregnanolone serum concentrations across the menstrual cycle in women with severe premenstrual syndrome and controls.

BACKGROUND: Neurosteroids have been proposed to play an important role in the interaction between alcohol and GABA(A) receptors and for the symptomatology of premenstrual dysphoric disorder (PMDD). The primary aim of this study was to investigate possible alcohol-induced changes in allopregnanolone serum concentrations across different menstrual cycle phases in women with severe premenstrual syndrome (PMS) and controls. METHODS: The allopregnanolone and cortisol responses to a low-dose of alcohol were evaluated in 14 women with and 12 women without severe premenstrual syndrome in the follicular and late luteal phases. The effect of a 30-min intravenous alcohol infusion (0.2 g/kg) on allopregnanolone and cortisol serum concentrations was compared to placebo, and compared between cycle phases and groups. Blood samples for measuring allopregnanolone were taken at baseline 25, 55, and 75 min after the start of the alcohol infusion. RESULTS: In the late luteal phase, the alcohol infusion decreased allopregnanolone levels, compared to baseline levels as well as to placebo. The difference in allopregnanolone levels between alcohol and placebo was evident 25 min (P < 0.01), 55 min (P < 0.01), and 75 min (P < 0.05) after start of the infusion. There was no change in allopregnanolone levels during the alcohol infusion in the follicular phase. Also, no difference in alcohol-induced allopregnanolone response between PMS patients and control subjects was detected. Cortisol levels declined during both the placebo and alcohol infusion, but did not differ with respect to which infusion had been given. CONCLUSION: During the late luteal phase, independent of PMS diagnosis, the low-dose alcohol infusion resulted in decreasing peripheral allopregnanolone levels.

3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone.

Allopregnanolone is a progesterone metabolite and GABA-A receptor modulator with benzodiazepine like effects, including decreased learning and memory. In vitro 3beta-hydroxypregnane steroids antagonize allopregnanolone-induced effects, but no antagonism has been shown in vivo. Our purpose was to evaluate 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) as a blocker of allopregnanolone-induced effects in vivo and in vitro in rats. We tested adult male Wistar rats in the Morris water maze 8 min after daily injections (i.v.) of allopregnanolone 2 mg/kg (n = 21); allopregnanolone : UC1011 2 : 6 (n = 7), 2 : 8 (n = 7), 2 : 20 (n = 14) mg/kg; UC1011 20 mg/kg (n = 14); or vehicle (10% 2-hydroxypropyl-beta-cyclodextrin, n = 4). Studies of chloride ion uptake into cortical and hippocampal membrane preparations were performed. The latency to find the hidden platform was still high in the allopregnanolone-injected group on day 6. Day 3-6 rats injected with allopregnanolone and UC1011 (2 : 20 mg/kg) had lower latency (P < 0.05), compared to the allopregnanolone-injected group. The group that only received UC1011 learned the location of the platform as fast as the controls. There was no significant difference in swim speed between groups. The time spent swimming close to the pool wall was in the allopregnanolone : UC1011 group (2 : 20 mg/kg) significantly decreased (P < 0.05, day 3-6), compared to the allopregnanolone-injected group. The increased chloride ion uptake induced by increasing dosage of allopregnanolone in the presence of 10 micro m GABA was significantly decreased with UC1011 (P < 0.01), in both cortical and hippocampal homogenates. In conclusion, UC1011 can via antagonism at the GABA-A receptor reduce the negative allopregnanolone effect on learning in the water maze.

Pathogenesis in menstrual cycle-linked CNS disorders.

That 3alpha-hydroxy-5alpha/beta-pregnane steroids (GABA steroids) have modulatory effects on the GABA-A receptor is well known. In behavioral studies in animals high exogenous dosages give concentrations not usually reached in the brain under physiological conditions. Animal and human studies show that GABA-A receptor-positive modulators like barbiturates, benzodiazepines, alcohol, and allopregnanolone have a bimodal effect. In pharmacological concentrations they are CNS depressants, anesthetic, antiepileptic, and anxiolytic. In low dosages and concentrations, reached endogenously, they can induce adverse emotional reactions in up to 20% of individuals. GABA steroids can also induce tolerance to themselves and similar substances, and rebound occurs at withdrawal. Menstrual cycle-linked disorders can be understood by the concept that they are caused by the action of endogenously produced GABA-steroids through three mechanisms: (a) direct action, (b) tolerance induction, and (c) withdrawal effect. Examples of symptoms and disorders caused by the direct action of GABA steroids are sedation, memory and learning disturbance, clumsiness, increased appetite, worsening of petit mal epilepsy, negative mood as tension, irritability and depression during hormone treatments, and the premenstrual dysphoric disorder (PMDD). A continuous exposure to GABA steroids causes tolerance, and women with PMDD are less sensitive to GABA-A modulators. A malfunctioning GABA-A receptor system is related to stress sensitivity, concentration difficulties, loss of impulse control, irritability, anxiety, and depression. An example of withdrawal effect is "catamenial epilepsy," when seizures increase during menstruation after the withdrawal of GABA steroids. Similar phenomena occur at stress since the adrenals produce GABA steroids during stress.