Changes in Progesterone Metabolites in the Hippocampus Can Modulate Open Field and Forced Swim Test Behavior of Proestrous Rats

doi:10.1006/hbeh.2002.1763

Hormones and Behavior

Volume 41, Issue 3, May 2002, Pages 306-315

https://doi.org/10.1006/hbeh.2002.1763 Get rights and content

Abstract

The purpose of these experiments was to test the hypothesis that attenuating the endogenous increase of the 5α-reduced progesterone metabolite 5α-pregnan-3α-ol-20-one (3α,5α-THP) in the hippocampus will alter anxiety and depression behavior of proestrous rats. In Experiment 1, anxiety (open field) and depression (forced swim test) behavior was compared of rats that should have high (proestrous) and low (diestrous and male rats) endogenous hippocampal 3α,5α-THP. Proestrous rats exhibited more anxiolytic-like (increased central entries in the open field) and anti-depressant-like (less immobility in the forced swim test) behavior than diestrous or male rats. In Experiments 2 and 3, respectively, systemic and intrahippocampal finasteride, a 5α-reductase inhibitor which attenuates progesterone's metabolism to 3α,5α-THP, versus vehicle administration to proestrous rats was compared for effects on open field and forced swim test behavior. Systemic or intrahippocampal finasteride decreased central entries in the open field and increased immobility in the forced swim tests compared to vehicle administration. In Experiment 4, the effects of systemic and intrahippocampal finasteride vs vehicle administration on hippocampal 3α,5α-THP of proestrous rats was examined. Finasteride, SC or intrahippocampally, reduced 3α,5α-THP in the hippocampus compared to vehicle administration. Together these data suggest that variations in 3α,5α-THP levels in the hippocampus may mitigate proestrous changes in anxiety and depressive behavior of cycling rats.

References (64)

Y. Akwa et al.
The amygdala mediates the anxiolytic-like effect of the neurosteroid allopregnanolone in rat
Behav. Brain Res.
(1999)
J. Archer
Rodent sex differences in emotional and related behaviors
Behav. Biol.
(1975)
M. Bernardi et al.
Influence of ovariectomy, estradiol and progesterone on the behavior of mice in an experimental model of depression
Physiol. Behav.
(1989)
D. Bitran et al.
Anxiolytic effects of the neuroactive steroid pregnanolone (3α-OH-5β-pregnan-20-one) after microinjection in the dorsal hippocampus and lateral septum
Brain Res.
(1999)
D. Bitran et al.
Anxiolytic effects of 3α-hydroxy-5α<β>-pregnan-20-one-endogenous metabolites of progesterone that are active at the GABA_A receptor
Brain Res.
(1991)
D.A. Blizard et al.
Sex differences in open-field behavior in the rat: The inductive and activational role of gonadal hormones
Physiol. Behav.
(1975)
M.D. Brot et al.
The anxiolytic-like effects of the neurosteroid allopregnanolone: Interactions with GABA_A receptors
Eur. J. Pharmacol.
(1997)
C.M. Contreras et al.
Desipramine restricts estral cycle oscillations in swimming
Prog. Neuropsychopharmacol. Biol. Psychiatry
(1998)
A. Fernandez-Guasti et al.
Chronic treatment with desipramine induces an estrous cycle-dependent anxiolytic-like action in the burying behavior, but not in the elevated plus-maze test
Pharmacol. Biochem. Behav.
(1999)
A. Fernandez-Guasti et al.
The actions of diazepam and serotonergic anxiolytics vary according to the gender and the estrous cycle phase
Pharmacol. Biochem. Behav.
(1990)

A. Fernandez-Guasti et al.

Changes in burying behavior during the estrous cycle—Effect of estrogen and progesterone

Psychoneuroendocrinol.

(1992)

A. Fernandez-Guasti et al.

Sexual differentiation modifies the allopregnanolone anxiolytic actions in rats

Psychoneuroendocrinol.

(1999)

C.A. Frye et al.

The neurosteroids, progesterone and 3α,5α-THP, enhance sexual motivation, receptivity, and proceptivity in female rats

Brain Res.

(1998)

C.A. Frye et al.

Hormonal milieu affects tailflick latency in female rats and may be attenuated by access to sucrose

Physiol. Behav.

(1992)

C.A. Frye et al.

Progesterone metabolites, effective at the GABA_A receptor complex, attenuate pain sensitivity in rats

Brain Res.

(1994)

C.A. Frye et al.

Estrous cycle and sex differences in performance on anxiety tasks coincide with increases in hippocampal progesterone and 3α,5α-THP

Pharmacol. Biochem. Behav.

(2000)

M.A. Gallo et al.

Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: A possible rat model of PMS anxiety

Pharmacol. Biochem. Behav.

(1993)

R. Ganesan

The aversive and hypophagic effects of estradiol

Physiol. Behav.

(1994)

A.L. Johnston et al.

Sex differences in animal tests of anxiety

Physiol. Behav.

(1991)

R.B. Kanarek et al.

Role of gonadal hormones in diet selection and food utilization in female rats

Physiol. Behav.

(1980)

C.K. Kellogg et al.

Reduced progesterone metabolites are not critical for plus-maze performance of lactating female rats

Pharmacol. Biochem. Behav.

(1999)

R.T. Khisti et al.

Serotonergic agents modulate antidepressant-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice

Brain Res.

(2000)

R.T. Khisti et al.

Antidepressant-like effect of the neurosteroid 3α-hydroxy-5α-pregnan-20-one in mice forced swim test

Pharmacol. Biochem. Behav.

(2000)

L. Martinez-Mota et al.

Interaction of desipramine with steroid hormones on experimental anxiety

Psychoneuroendocrinol.

(2000)

M.M. McCarthy et al.

Infusions of diazepam and allopregnanolone into the midbrain central gray facilitate open-field behavior and sexual receptivity in female rats

Horm. Behav.

(1995)

S. Mora et al.

Effects of the estrous cycle and ovarian hormones on behavioral indices of anxiety in female rats

Psychoneuroendocrinol.

(1996)

M. Okada et al.

Influences of ovariectomy and continuous replacement of 17β-estradiol on the tail skin temperature and behavior in the forced swimming test in rats

Jpn. J. Pharmacol.

(1997)

W.P. Pare et al.

Sex differences and stress response of WKY rats

Physiol. Behav.

(1993)

R.H. Purdy et al.

Radioimmunoassay of 3α-hydroxy-5α-pregnan-20-one in rat and human plasma

Steroids.

(1990)

J.F. Rodriguez-Sierra et al.

Anxiolytic effects of progesterone are sexually dimorphic

Life Sci.

(1986)

J.W. Smythe et al.

The interaction between prenatal stress and neonatal handling on nociceptive response latencies in male and female rats

Physiol. Behav.

(1994)

Cited by (239)

Neurosteroid influence on affective tone
2023, Neuroscience and Biobehavioral Reviews
Affective disorders such as depression and anxiety are among the most prevalent psychiatric illnesses and causes of disability worldwide. The recent FDA-approval of a novel antidepressant treatment, ZULRESSO® (Brexanolone), a synthetic neurosteroid has fueled interest into the role of neurosteroids in the pathophysiology of depression as well as the mechanisms mediating the antidepressant effects of these compounds. The majority of studies examining the impact of neurosteroids on affective states have relied on the administration of exogenous neurosteroids; however, neurosteroids can also be synthesized endogenously from cholesterol or steroid hormone precursors. Despite the well-established influence of exogenous neurosteroids on affective states, we still lack an understanding of the role of endogenous neurosteroids in modulating affective tone. This review aims to summarize the current literature supporting the influence of neurosteroids on affective states in clinical and preclinical studies, as well as recent evidence suggesting that endogenous neurosteroids may set a baseline affective tone.
Role of sirtuin1 in impairments of emotion-related behaviors in mice with chronic mild unpredictable stress during adolescence
2022, Physiology and Behavior
Long-term exposure to physical and/or psychosocial stress during early life and/or adolescence increases the risk of psychiatric disorders such as major depressive disorder and anxiety disorders. However, the molecular mechanisms underlying early stress-induced brain dysfunction are poorly understood. In the present study, mice at 4 weeks old were subjected to chronic mild unpredictable stress (CMUS) for 4 weeks, and subsequently to assays of emotion-related behaviors. Thereafter, they were sacrificed and their brains were collected for real-time quantitative polymerase chain reaction (RT-qPCR). Mice with CMUS during adolescence showed despair behavior, anxiety-like behavior, social behavior deficits, and anhedonia in forced-swim, marble-burying, social interaction, and sucrose preference tests, respectively. Additionally, RT-qPCR revealed that the expression levels of sirtuin1 (SIRT1), a NAD⁺-dependent deacetylase that mediates stress responses, were down-regulated in the prefrontal cortex and hippocampus of mice with CMUS compared with control mice. Next, to investigate the pathophysiological role of decreased Sirt1 expression levels in stress-induced behavioral deficits, we assessed the effects of resveratrol, a pharmacological activator of SIRT1, in mice exposed to CMUS. Chronic treatment with resveratrol prevented CMUS-induced social behavior deficits and depression-like behaviors. These results suggest that CMUS during adolescence decreases Sirt1 expression in the brain, leading to deficits in emotional behavior. Accordingly, SIRT1 activators, such as resveratrol, may be preventive agents against abnormalities in emotional behavior following stress during an immature period.
Deficiency of the circadian clock gene Rev-erbα induces mood disorder-like behaviours and dysregulation of the serotonergic system in mice
2022, Physiology and Behavior
Mood disorders such as depression, anxiety, and bipolar disorder are highly associated with disrupted daily rhythms of activity, which are often observed in shift work and sleep disturbance in humans. Recent studies have proposed the REV-ERBα protein as a key circadian nuclear receptor that links behavioural rhythms to mood regulation. However, how the Rev-erbα gene participates in the regulation of mood remains poorly understood. Here, we show that the regulation of the serotonergic (5-HTergic) system, which plays a central role in stress-induced mood behaviours, is markedly disrupted in Rev-erbα^−/− mice. Rev-erbα^−/− mice exhibit both negative and positive behavioural phenotypes, including anxiety-like and mania-like behaviours, when subjected to a stressful environment. Importantly, Rev-erbα^−/− mice show a significant decrease in the expression of a gene that encodes the rate-limiting enzyme of serotonin (5-HT) synthesis in the raphe nuclei (RN). In addition, 5-HT levels in Rev-erbα^−/− mice are significantly reduced in the prefrontal cortex, which receives strong inputs from the RN and controls stress-related behaviours. Our findings indicate that Rev-erbα plays an important role in controlling the 5-HTergic system and thus regulates mood and behaviour.
Swimming exercise prevents hippocampal dendritic spine changes and memory loss caused by aging: An application of a new semi-automated spine analysis software
2022, Molecular and Cellular Neuroscience
Dendritic spines are small, ratchet-like protrusions on neuronal dendrites that form synapses for receiving neuronal messages. Dendritic spine morphology is associated with synapse function. If neurons degrade or are damaged, the spine morphology of neurons changes. Given that most commercially available spine analysis software is expensive and complex, this study investigated a semi-automated spine analysis software, CTSpine, and used previously published data to verify the accuracy of the analysis results of this software. We also applied CTSpine to understand whether aging causes alterations in the hippocampal spine morphology and whether physical exercise can impede dendritic spine changes in 20 male Sprague Dawley rats. The spines of pyramidal cells in the hippocampal Cornu Ammonis 1 (CA1) region in the aging group were more enriched in filopodium type pattern than those in the control group, whereas the spines of the exercised aging group showed a similar pattern to that of the control. No significant changes were observed in neuronal dendritic spines in other hippocampal regions. However, long-term hippocampal memory was considerably decreased in the aging group, which was reversed to some extent in the exercised aging group. CTSpine, a self-developed semi-automatic spine analysis software, showed results similar to those noted in published data and can be effectively applied to the study of dendritic patterns, including neurodevelopment and disease.
Sex hormone fluctuation and increased female risk for depression and anxiety disorders: From clinical evidence to molecular mechanisms
2022, Frontiers in Neuroendocrinology
Women are at twice the risk for anxiety and depression disorders as men are, although the underlying biological factors and mechanisms are largely unknown. In this review, we address this sex disparity at both the etiological and mechanistic level. We dissect the role of fluctuating sex hormones as a critical biological factor contributing to the increased depression and anxiety risk in women. We provide parallel evidence in humans and rodents that brain structure and function vary with naturally-cycling ovarian hormones. This female-unique brain plasticity and associated vulnerability are primarily driven by estrogen level changes. For the first time, we provide a sex hormone-driven molecular mechanism, namely chromatin organizational changes, that regulates neuronal gene expression and brain plasticity but may also prime the (epi)genome for psychopathology. Finally, we map out future directions including experimental and clinical studies that will facilitate novel sex- and gender-informed approaches to treat depression and anxiety disorders.
Insights overview on the possible protective effect of chitosan nanoparticles encapsulation against neurotoxicity induced by carbendazim in rats
2022, NeuroToxicology
Carbendazim (CBZ) contamination of food and water is a principal factor in many negative impacts on public health. Nanoencapsulation of agrochemicals by nontoxic polymers as chitosan nanoparticles (CS-NPs) is one of the most applications of nanotechnology in agriculture. Despite its many advantages, such as it provides controlled release property, more stability and solubility of the active ingredient, it is not authorized to be used in the market because there are no adequate studies on the nano pesticides induced toxicity on experimental animals. So, we aim to study the possible impacts of CBZ-loading CS-NPs on the whole brain of rats and to explain its mechanism of action. 20 male Wistar rats were partitioned into 4 groups as follows: Group (1), normal saline; group (2), 5 mg/kg CS-NPs; group (3), 300 mg/kg CBZ; group (4) 300 mg/kg CS/CBZ-NCs. After 28 days, some neurobehavioral parameters were assessed to all rats then euthanization was done to collect the brain. Our results revealed that CBZ prompted neurotoxicity manifested by severe neurobehavioral changes and a significant increase of MDA with a decrease of GSH and CAT in brain tissue. In addition, there were severe neuropathological alterations confirmed by immunohistochemistry which showed strong bax, GFAP, and TNF-ὰ protein expression in some brain areas. CBZ also induced apoptosis manifested by up-regulation of JNK and P53 with down-regulation of Bcl-2 in brain tissue. Otherwise, encapsulation of CBZ with CS-NPs could reduce CBZ-induced neurotoxicity and improve all studied toxicological parameters. We recommend using CBZ-loading CS-NPs as an alternative approach for fungicide application in agricultural and veterinary practices but further studies are needed to ensure its safety on other organs.

View all citing articles on Scopus

¹: To whom correspondence and reprint requests should be addressed. E-mail: [email protected].

View full text

Regular ArticleChanges in Progesterone Metabolites in the Hippocampus Can Modulate Open Field and Forced Swim Test Behavior of Proestrous Rats

Abstract

Behav. Brain Res.

Behav. Biol.

Physiol. Behav.

Brain Res.

Brain Res.

Physiol. Behav.

Eur. J. Pharmacol.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Psychoneuroendocrinol.

Psychoneuroendocrinol.

Brain Res.

Physiol. Behav.

Brain Res.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Physiol. Behav.

Physiol. Behav.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Brain Res.

Pharmacol. Biochem. Behav.

Psychoneuroendocrinol.

Horm. Behav.

Psychoneuroendocrinol.

Jpn. J. Pharmacol.

Physiol. Behav.

Steroids.

Life Sci.

Physiol. Behav.

Regular Article
Changes in Progesterone Metabolites in the Hippocampus Can Modulate Open Field and Forced Swim Test Behavior of Proestrous Rats