Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility

doi:10.1016/j.pbb.2007.05.017

Pharmacology Biochemistry and Behavior

Volume 87, Issue 4, October 2007, Pages 412-419

https://doi.org/10.1016/j.pbb.2007.05.017 Get rights and content

Abstract

Withdrawal from high levels of progesterone in rodents has been proposed as a model for premenstrual syndrome or postpartum depression. Forced swim test (FST) immobility, used to model depression, was assessed in intact female DBA/2J mice following progesterone withdrawal (PWD) or treatment with the 5α-reductase inhibitor finasteride. Following 5 daily progesterone injections (5 mg/kg IP) FST immobility increased only in mice withdrawn for 3 days (p < .05). In another experiment, 3 days of PWD significantly decreased levels of progesterone compared to 0 days of withdrawal, but progesterone levels at 3 days of PWD did not differ from vehicle-treated controls. In a final study, mice received daily injections of progesterone (5 mg/kg IP) for 8 days, with 0 mg/kg, 50 mg/kg, or 100 mg/kg finasteride co-administered for the last three days. Mice that received 100 mg/kg finasteride, but not 50 mg/kg finasteride, displayed increased FST immobility. PWD and finasteride treatment, both of which reduce allopregnanolone levels, were associated with increased FST immobility in female DBA/2J mice. These findings suggest that decreased levels of the GABAergic neurosteroid allopregnanolone contribute to symptoms of PWD. Future studies of PWD may provide information about human conditions that are associated with hormone changes such as premenstrual syndrome or postpartum depression.

Section snippets

Animals

Female DBA/2J mice were obtained from The Jackson Laboratory (Davis, CA) and housed in the Veterinary Medical Unit at the Veterans Affairs Medical Center (VAMC) in Portland, OR. Mice were housed four to a cage except two cages (3 mice/cage) in Experiment 1a. All mice were housed in Maxi-Miser #1 cages (Thoren Caging Systems, Hazelton, PA) with 0.25-in Bed-o'cobs bedding (Andersons Inc., Maumee OH). All mice were housed in a temperature controlled room (21 ± 1 °C). Throughout each experiment, mice

Experiment 1a: time course of PWD, measured by FST behavior

ANOVA was used to compare group means of FST immobility (Fig. 1). The omnibus test revealed that depression-like behavior differed among treatment groups, F_4,60 = 3.97, p < .05. Tukey HSD comparisons revealed that the 3 d PWD group exhibited significantly more immobility in the FST than each of the other groups. No other difference was determined among these groups.

Experiment 1b: time course of progesterone levels during PWD

ANOVA was performed on plasma progesterone concentrations of blood collected from mice that received one 5 mg/kg progesterone

Discussion

These experiments were designed to adapt a previously described PWD procedure for behavioral analysis, and to determine whether the behavioral effect of PWD could be replicated by withdrawing 5α-reduced neurosteroids (such as ALLO). Experiment 1a determined that three days of PWD was required to detect a significant increase in FST immobility. This finding is consistent with recent reports of delayed increases in FST immobility following steroid withdrawal (Bekku et al., 2007, Stoffel and

Acknowledgement

This work was supported by National Institutes of Health grants AA10760 and AA12439, and a Merit Award from the Department of Veterans affairs (D. A. F.). E. H. B. was also supported by the NIH training grant T32-AA07468 (awarded to Dr. Christopher L. Cunningham), and by the Nancy and Dodd Fischer Scholarship, administered by the Portland, OR chapter of the ARCS Foundation. Drs. Suzanne H. Mitchell and John C. Crabbe and two anonymous faculty members provided valuable feedback on some of the

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Progesterone was known to be increased following stress [6,7], and some literature suggested that progesterone might modify 5-HT1A receptors and act as a sedative following stress [6]. Animal literature specifically on the premenstrual period produced some evidence that high progesterone levels might induce mood and anxiety symptoms [8], but other studies showed that progesterone withdrawal [9] or progesterone antagonists (which mimic progesterone withdrawal and/or decreased progesterone receptor activity) [10,11] could lead to increased depressive-like behaviors. Human literature was also mixed.
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However, note that enhancement of tonic inhibition in models of absence epilepsy aggravates the condition by promoting thalamic burst firing (Cope et al., 2009; Errington et al., 2011). Blockade of neurosteroid production by inhibition of 5α-reductase with finasteride increases depression-like behaviors in experimental animal models (Walf et al., 2006; Beckley and Finn, 2007) and in some men treated for male pattern hair loss i.e. “finasteride syndrome” (Locci and Pinna, 2017; Melcangi et al., 2017). Allopregnanolone levels are negatively correlated with depression-like behaviors (Walf et al., 2006).
In the 1980s particular endogenous metabolites of progesterone and of deoxycorticosterone were revealed to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA_A receptor (GABA_AR). These reports were followed by the discovery that such steroids may be synthesised not only in peripheral endocrine glands, but locally in the central nervous system (CNS), to potentially act as paracrine, or autocrine “neurosteroid” messengers, thereby fine tuning neuronal inhibition. These discoveries triggered enthusiasm to elucidate the physiological role of such neurosteroids and explore whether their levels may be perturbed in particular psychiatric and neurological disorders. In preclinical studies the GABA_AR-active steroids were shown to exhibit anxiolytic, anticonvulsant, analgesic and sedative properties and at relatively high doses to induce a state of general anaesthesia. Collectively, these findings encouraged efforts to investigate the therapeutic potential of neurosteroids and related synthetic analogues. However, following over 30 years of investigation, realising their possible medical potential has proved challenging. The recent FDA approval for the natural neurosteroid allopregnanolone (brexanolone) to treat postpartum depression (PPD) should trigger renewed enthusiasm for neurosteroid research. Here we focus on the influence of neuroactive steroids on GABA-ergic signalling and on the challenges faced in developing such steroids as anaesthetics, sedatives, analgesics, anticonvulsants, antidepressants and as treatments for neurodegenerative disorders.
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Prevalence of postpartum depression (PPD) ranges from 10 to 15 % of parturients. The impact of the PPD is major on the maternal bond and the health of both mother and child. Its physiopathological mechanisms appear to differ from other types of depression. Today, pharmacotherapy is based on nonspecific treatment, and recent therapeutic advances in this field require a comprehensive approach of the implication of the GABAergic system in the development of PPD. Neurosteroid levels during pregnancy and after parturition and the GABA-A-r modulation are thought to be involved in PPD.
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Disability to modulate GABA-A-r expression during pregnancy and restore its previous state after parturition appears to trigger PPD. The GABAergic system is a promising pharmacotherapy target. From preclinical to clinical studies for about twenty years the GABAergic system has been incriminated and targeted in this challenging mental disease.

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Inhibition of progesterone metabolism mimics the effect of progesterone withdrawal on forced swim test immobility

Abstract

Section snippets

Animals

Experiment 1a: time course of PWD, measured by FST behavior

Experiment 1b: time course of progesterone levels during PWD

Discussion

Acknowledgement

Eur J Pharmacol

Neurosci Biobehav Rev

Brain Res Bull

Neuropharmacology

Trends Pharmacol Sci

Neuroscience

Pharmacol Ther

Pharmacol Biochem Behav

Horm Behav

Brain Res

Behav Brain Res

Psychoneuroendocrinology

Neuropharmacology

Horm Behav

Eur J Pharmacol

Obstet Gynecol

Biol Psychiatry

Epilepsy Behav

Pharmacol Biochem Behav

Alcohol

J Affect Disord

Physiol Behav

Factors producing a menopausal depressive-like state in mice following ovariectomy

Psychopharmacology (Berl)

Disadaptive disorders in women: allopregnanolone, a sensitive steroid

Gynecol Endocrinol

Different brain activation patterns to pain and pain-related unpleasantness during the menstrual cycle

Anesthesiology

The media construct a menstrual monster: a content analysis of PMS articles in the popular press

Women Health

Neurosteroids: 3α-hydroxy-5α-pregnan-20-one and its precursors in the brain, plasma, and steroidogenic glands of male and female rats

Endocrinology

Withdrawal from the endogenous steroid progesterone results in GABAA currents insensitive to benzodiazepine modulation in rat CA1 hippocampus

J Neurophysiol

Progesterone enhances ethanol-induced modulation of mesocortical dopamine neurons: antagonism by finasteride

J Neurochem

Withdrawal from the endogenous steroid progesterone results in GABA_A currents insensitive to benzodiazepine modulation in rat CA1 hippocampus