The impact of sex as a biological variable in the search for novel antidepressants

Williams, Alexia; Trainor, Brian C.

doi:10.1016/j.yfrne.2018.05.003

Cited by 36 publications

(18 citation statements)

References 183 publications

(212 reference statements)

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“…Female mice and rats have been reported to be less sensitive than males in their responses to kappa opioid agonists and antagonists (Russell et al, 2014; Abraham et al, 2018; Laman-Maharg et al, 2018; Williams and Trainor, 2018). These sex differences raise important questions about the utility of kappa antagonists in the treatment of stress-disorders in women.…”

Section: Resultsmentioning

confidence: 99%

Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation

2019

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Kappa receptor activation by dynorphins contributes to the anxiogenic, dysphoric, and cognitive disrupting effects of repeated stress, suggesting that kappa receptor antagonists might have therapeutic utility in the treatment of stress disorders. Three classes of kappa antagonists have been distinguished: non-selective, selective-competitive (readily reversible), and non-competitive (receptor-inactivating); however, which would be the most effective medication has not been established. To assess the utility of receptor inactivating antagonists, we tested the effects of a range of doses in both male and female mice. As previously established, the antinociceptive effects of the kappa agonist U50,488 were blocked by a single injection of the long-acting antagonist norbinatorphimine (norBNI) (10 mg/kg i.p.) in male mice. Ten to 20-fold lower doses of norBNI were ineffective after a single administration, but daily administration of 1.0 or 0.5 mg/kg for 5 days completely blocked U50,488 antinociceptive effects. Daily administration of 0.1 mg/kg norBNI produced slowly accumulating inhibition and completely blocked the antinociceptive effect of U50,488 after 20–30 days. Estrogen reduces female sensitivity to kappa opioid effects, but 30 days of 0.1 mg/kg norBNI completely blocked U50,488 analgesia in ovariectomized mice. Receptor inactivation in both male and female mice treated for 30 days with 0.1 mg/kg norBNI persisted for at least 1-week. These results suggest that receptor-inactivating kappa antagonists are effective in both males and females when given at 100-fold lower doses than typically administered in preclinical studies. The enhanced safety of this low-dosing protocol has important clinical implications if receptor inactivating kappa antagonists advance in medication development.

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Section: Resultsmentioning

confidence: 99%

Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation

2019

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“…Given evidence for a stimulatory role of the DYN/KOR system in negative affect and affective disorders ( Knoll and Carlezon, 2010 ; Tejeda et al, 2012 ; Van't Veer and Carlezon, 2013 ), it might be expected that the DYN/KOR system would be more sensitive in females than males. However, the few studies that have examined sex differences in responsivity of the DYN/KOR system have generally found females to be less sensitive than males to both activation and inhibition of the DYN/KOR system, both in terms of changes in pain response and affect [see reviews by ( Becker and Chartoff, 2018 ; Chartoff and Mavrikaki, 2015 ; Williams and Trainor, 2018 )]. While the underlying mechanisms driving these sex differences are not well understood, a number of differences have been reported regarding the role of the DYN/KOR system in females, including polymorphisms in the prodynorphin (pDYN) gene, interactions with the melanocortin 1 receptor (MC1R) at the genetic level, heterodimerization of KORs and mu opioid receptors (MORs), and unique interactions with gonadal hormones ( Chartoff and Mavrikaki, 2015 ; Chartoff et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats

Spear

Diaz

2018

Neurobiology of Stress

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The dynorphin/kappa opioid receptor (DYN/KOR) system has been identified as a primary target of stress due to behavioral effects, such as dysphoria, aversion, and anxiety-like alterations that result from activation of this system. Numerous adaptations in the DYN/KOR system have also been identified in response to stress. However, whereas most studies examining the function of the DYN/KOR system have been conducted in adult rodents, there is growing evidence suggesting that this system is ontogenetically regulated. Likewise, the outcome of exposure to stress also differs across ontogeny. Based on these developmental similarities, the objective of this study was to systematically test effects of a selective KOR agonist, U-62066, on various aspects of social behavior across ontogeny in non-stressed male and female rats as well as in males and females with a prior history of repeated exposure to restraint (90 min/day, 5 exposures). We found that the social consequences of repeated restraint differed as a function of age: juvenile stress produced substantial increases in play fighting, whereas adolescent and adult stress resulted in decreases in social investigation and social preference. The KOR agonist U-62066 dose-dependently reduced social behaviors in non-stressed adults, producing social avoidance at the highest dose tested, while younger animals displayed reduced sensitivity to this socially suppressing effect of U-62066. Interestingly, in stressed animals, the socially suppressing effects of the KOR agonist were blunted at all ages, with juveniles and adolescents exhibiting increased social preference in response to certain doses of U-62066. Taken together, these findings support the hypothesis that the DYN/KOR system changes with age and differentially responds and adapts to stress across development.

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“…14 For example, many studies demonstrate that sex can moderate key outcomes. [15][16][17][18][19] Ignoring sex in these studies would have led to very different conclusions. In an effort to improve the rigor and reproducibility of research studies, the National Institutes of Health (NIH) now requires all NIH-funded research to consider sex as a biological variable (SABV).…”

Section: Scientific Concernsmentioning

confidence: 92%

Filling the Regulatory Gap: Potential Role of Institutional Review Boards in Promoting Consideration of Sex as a Biological Variable

Duffy

Ziolek²,

Epperson

2020

Journal of Women's Health

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Consideration of sex differences in biomedical research is crucial to ensure the safety and effectiveness of drugs and devices for both sexes and to improve the rigor and reproducibility of scientific discoveries. Historically, women were underrepresented in clinical research and sex differences typically were not considered. The U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH) have played a role in improving the representation of women in clinical trials and in encouraging the consideration of sex differences. As it is not appropriate for all studies to be reviewed by the FDA nor do all studies have NIH funding, this results in a regulatory gap. We propose that local institutional review boards (IRBs) and institutional animal care and use committees (IACUCs) provide greater oversight by encouraging researchers to consider sex as a biological variable (SABV) during protocol review. In this perspective article, we review how FDA and NIH policies have fostered change and highlight how IRBs and IACUCs could encourage investigators to consider SABV.

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The impact of sex as a biological variable in the search for novel antidepressants

Cited by 36 publications

References 183 publications

Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation

Repeated Administration of Norbinaltorphimine Produces Cumulative Kappa Opioid Receptor Inactivation

Stress alters social behavior and sensitivity to pharmacological activation of kappa opioid receptors in an age-specific manner in Sprague Dawley rats

Filling the Regulatory Gap: Potential Role of Institutional Review Boards in Promoting Consideration of Sex as a Biological Variable

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