Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology

Bangasser, Debra A.; Curtis, Andre L.; Reyes, Beverly A.S.; Bethea, Thelma; Parastatidis, Ioannis; Ischiropoulos, Harry; Bockstaele, Elisabeth J. Van; Valentino, Rita J.

doi:10.1038/mp.2010.66

Cited by 323 publications

(408 citation statements)

References 59 publications

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“…Crh secretion is sexually dimorphic (Bangasser and Valentino, 2012;Iwasaki-Sekino et al, 2009), and Crhr1 signaling is more sensitive in females as G-protein coupling is increased and receptor internalization is decreased compared to males (Bangasser et al, 2010). However, we show that gene expression of the selected candidate genes is independent of Crhr1.…”

Section: Discussionmentioning

confidence: 65%

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Hippocampal gene expression induced by cold swim stress depends on sex and handling

Bohacek

Manuella

Roszkowski

et al. 2015

Psychoneuroendocrinology

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Summary: Stress-related disorders such as PTSD and depression are more prevalent in women than men. One reason for such discordance may be that brain regions involved in stress responses are more sensitive to stress in females. Here, we compared the effects of acute stress on gene transcription in the hippocampus of female and male mice, and also examined the involvement of two key stress-related hormones, corticosterone and corticotropin releasing hormone (Crh). Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), we measured gene expression of Fos, Per1 and Sgk1 45 min after exposure to brief cold swim stress. Stress induced a stronger increase in Fos and Per1 expression in females than males. The handling control procedure increased Fos in both sexes, but occluded the effects of stress in males. Further, handling increased Per1 only in males. Sgk1 was insensitive to handling, and increased in response to stress similarly in males and females. The transcriptional changes observed after swim stress were not mimicked by corticosterone injections, and the stress-induced increase in Fos, Per1 and Sgk1 could neither be prevented by pharmacologically blocking glucocorticoid receptor (GR) nor by blocking Crh receptor 1 (Crhr1) before stress exposure. Finally, we demonstrate that the effects are stressor-specific, as the expression of target genes could not be increased by brief restraint stress in either sex. In summary, we find strong effects of acute swim stress on hippocampal gene expression, complex interactions between handling and sex, and a remarkably unique response pattern for each gene. Overall, females respond to a cold swim challenge with stronger hippocampal gene transcription than males, independent of two classic mediators of the stress response, corticosterone and Crh. These findings may have important implications for understanding the higher vulnerability of women to certain stress-related neuropsychiatric diseases. In summary, we find strong effects of acute swim stress on hippocampal gene expression, complex interactions between handling and sex, and a remarkably unique response pattern for each gene. Overall, females respond to a cold swim challenge with stronger hippocampal gene transcription than males, independent of two classic mediators of the stress response, corticosterone and Crh. These findings may have important implications for understanding the higher vulnerability of women to certain stress-related neuropsychiatric diseases.

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Section: Discussionmentioning

confidence: 65%

“…When acting through Crh receptor 1 (Crhr1), it mediates several of the rapid effects of acute stress in the hippocampus (Wang et al, 2013). Sex-differences in stress-induced gene regulation may therefore be due to differential responsiveness of the Crh system between sexes (Bangasser et al, 2010;Iwasaki-Sekino et al, 2009). …”

Section: Introductionmentioning

confidence: 99%

Hippocampal gene expression induced by cold swim stress depends on sex and handling

Bohacek

Manuella

Roszkowski

et al. 2015

Psychoneuroendocrinology

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“…Recent studies provide more insight into the role for the CRF system in sex-linked differences in stress responses. Notably, a swim stress induces association of CRF receptors to β-arrestin2 and receptor internalization in male rats; in contrast, the same stressor decreases the ratio of cytoplasmic-to-total CRF receptor levels in female rats, suggesting CRF receptor recruitment to the plasma membrane and increased stress susceptibility (Bangasser et al, 2010). Thus, ovarian hormones and/or sex-linked differences in plasma membrane CRF receptor availability might underlie the loss of resilience to the final stress exposure observed herein in the opiatewithdrawn female, but not male, CRF 2 − / − mice.…”

Section: Summary Of the Resultsmentioning

confidence: 99%

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Morisot

Rouibi

Contarino

2015

Neuropsychopharmacol

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Vulnerability to stressful life events is a hallmark of drug dependence that may persist long after cessation of drug intake and dramatically fuel key clinical features, such as deregulated up-shifted motivational states and craving. However, to date, no effective therapy is available for reducing vulnerability to stressful events in former drug users and drug-dependent patients, mostly because of poor knowledge of the mechanisms underlying it. In this study, we report that genetic inactivation of the stress-responsive corticotropin-releasing factor receptor-2 (CRF 2 − / − ) completely eliminates the reemergence of increased nonrewarded nose-pokes, reflecting up-shifted motivational states, triggered by ethological environmental stressors long after cessation of morphine administration in mice. Accordingly, CRF 2 receptor deficiency completely abolishes the increase in biomarkers of synthesis of major brain motivational substrates, such as ventral tegmental area (VTA) dopamine (DA) and amygdala γ-aminobutyric acid (GABA) systems, associated with the stress-induced reemergence of upshifted motivational states long after opiate withdrawal. Nevertheless, neither CRF 2 receptor deficiency nor long-term opiate withdrawal affects amygdala CRF or hypothalamus CRF expression, indicating preserved brain stress-coping systems. Moreover, CRF 2 receptor deficiency does not influence the locomotor or the anxiety-like effect of long-term opiate withdrawal. Thus, the present results reveal an essential and specific role for the CRF 2 receptor in the stress-induced reemergence of up-shifted motivational states and related alterations in brain motivational systems long after opiate withdrawal. These findings suggest new strategies for the treatment of the severe and longlasting vulnerability that inexorably follows drug withdrawal and hinder drug abstinence.

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“…We included Arrb2 based on the finding that in the locus coeruleus, female rats display lower levels of Arrb2, an important protein involved in the internalization of CRF-R1 receptors. 18,19 We recently presented a mechanistic hypothesis suggesting that nicotine withdrawal in females is mediated by an interaction between CRF, dopamine and estradiol systems in the NAcc. 11 Previous work has shown that dopamine levels are decreased in the NAcc during nicotine withdrawal.…”

Section: Original Investigationmentioning

confidence: 99%

Nicotine Withdrawal Increases Stress-Associated Genes in the Nucleus Accumbens of Female Rats in a Hormone-Dependent Manner

Torres

Pipkin

Ferree

et al. 2015

Nicotine & Tobacco Research

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IntroductionTobacco use is the number one cause of preventable deaths in the United States. 1 Of particular concern is the high rate of tobacco use among women, who are more susceptible to the negative health consequences of long-term smoking than men. 2 As a result, tobacco use is believed to be a major contributing factor to health disparities in women. In spite of the magnitude of the problem, surprisingly little is known about the underlying biological factors that promote tobacco relapse in females.Much work has suggested that stress promotes tobacco use in women. For example, women report more negative mood states, such as depression, anxiety, and intense craving during smoking abstinence than men. [3][4][5] Women also use more tobacco products and display lower quit rates relative to men. 6 Furthermore, women report that they maintain tobacco use to relieve intense withdrawal symptoms that emerge during abstinence, and they claim more often than men that the anxiety-reducing effects of cigarettes are the main reason for smoking. [7][8][9] Preclinical studies have shown that the behavioral and biological consequences of nicotine withdrawal are greater in female versus AbstractIntroduction: Previous work led to our hypothesis that sex differences produced by nicotine withdrawal are modulated by stress and dopamine systems in the nucleus accumbens (NAcc). We investigated our hypothesis by studying intact females to determine whether the mechanisms that promote withdrawal are ovarian-hormone mediated. Methods: Female rats were ovariectomized (OVX) or received sham surgery (intact) on postnatal day (PND 45-46). On PND 60, they received sham surgery (controls) or were prepared with nicotine pumps. Fourteen days later, half of the rats had their pumps removed (nicotine withdrawal) and the other half received sham surgery (nicotine exposure). Twenty-four hours later, the rats were tested for anxiety-like behavior using the elevated plus maze and light/dark transfer procedures. The NAcc was then dissected for analysis of several genes related to stress (CRF, UCN, CRF-R1, CRF-R2, CRF-BP, and Arrb2) or receptors for dopamine (Drd1 and Drd2) and estradiol (Esr2). Results: During withdrawal, intact females displayed an increase in anxiety-like behavior in both tests and CRF, UCN, and Drd1 gene expression. During nicotine exposure, intact females displayed a decrease in CRF-R1, CRF-R2, Drd3, and Esr2 gene expression and an increase in CRF-BP. This pattern of results was absent in OVX females. Conclusions: Nicotine withdrawal produced an increase in anxiety-like behavior and stress-associated genes in intact females that is distinct from changes produced by nicotine exposure. The latter effects were absent in OVX females, suggesting that stress produced by withdrawal is ovarianhormone mediated. These findings have important implications towards understanding tobacco use liability among females.

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Sex differences in corticotropin-releasing factor receptor signaling and trafficking: potential role in female vulnerability to stress-related psychopathology

Cited by 323 publications

References 59 publications

Hippocampal gene expression induced by cold swim stress depends on sex and handling

Hippocampal gene expression induced by cold swim stress depends on sex and handling

CRF2 Receptor Deficiency Eliminates the Long-Lasting Vulnerability of Motivational States Induced by Opiate Withdrawal

Nicotine Withdrawal Increases Stress-Associated Genes in the Nucleus Accumbens of Female Rats in a Hormone-Dependent Manner

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