Acute inhibition of kappa opioid receptors before stress blocks depression-like behaviors in California mice

Abstract

Kappa opioid receptors (KOR) are considered to be a promising therapeutic target for stress-induced psychiatric disorders such as anxiety and depression. Preclinical data show that KOR antagonists have greater efficacy if administered before stressful experiences as opposed to afterwards. However, almost all of these studies use long-acting antagonists, leaving it unclear whether inhibition of KOR after stress is required for efficacy. Here we show that administration of the short-acting KOR antagonist AZ-MTAB before episodes of social defeat stress block the induction of anhedonia (both males and females) and social avoidance responses (females) that persist two weeks after stress. In both males and females pre-stress AZ-MTAB treatment also blunted anticipatory autogrooming behavior immediately prior to the third episode of defeat. In contrast when AZ-MTAB was administered two weeks after defeat (immediately before behavior testing) in female California mice, it was ineffective at reversing anhedonia and social avoidance. These results suggest that short-acting KOR antagonists may have greater therapeutic potential if administered before exposure to psychosocial stressors.

The challenge hypothesis revisited: Focus on reproductive experience and neural mechanisms

“…In adults, losing social encounters has stronger long-term effects on social vigilance in females than males. Two weeks after losing experiences, females but not males exhibit avoidance and vigilance towards unfamiliar mice (Duque-Wilckens et al, 2018;Williams et al, 2018). Although this sex difference was still observed in gonadectomized individuals (Trainor et al, 2013), social vigilance may still be sensitive to gonadal hormones.…”

“…Social vigilance can be quantified in several ways. In a laboratory setting, the amount of time an animal spends oriented towards an unfamiliar individual is increased after unsuccessful competitive encounters (Duque-Wilckens et al, 2018;Williams et al, 2018). Interestingly, individuals with low social status often reduce feeding behavior to engage in visual scanning (Blumstein et al, 2001;Ekman, 1987;Shepherd et al, 2006), which is also an important form of antipredator behavior.…”

The Influence of Anxiety and Self-Efficacy on Statistics Performance: A Path Analysis

“…Physical stressors certainly exist, even in Western societies (e.g., malnutrition, infectious diseases), but psychosocial stressors are recognized as frequent precursors to onset of depressive and anxiety disorders (Juster, McEwen, & Lupien, 2010;McEwen, 2004McEwen, , 2005Slavich & Irwin, 2014). Second, the social defeat model is typically only effective with male rodents (although, see Harris et al, 2018;Takahashi et al, 2017;Williams et al, 2018) because males tend to be more aggressive than females (Solomon, 2017). However, women report experiencing depressive or anxiety symptoms two times more frequently than men (McLean, Asnaani, Litz, & Hofmann, 2011;Silverstein, 2002).…”

Impact of Pharmacological Manipulation of the κ-Opioid Receptor System on Self-grooming and Anhedonic-like Behaviors in Male Mice

“…Furthermore, this study also examined for the first time the pharmacology of k-receptor ligands in the mouse splash test, a simple and repeatable assay that measures self-grooming (Yalcin et al, 2008;Williams et al, 2018). Self-grooming in rodents is a highly regulated homeostatic behavior, mediated by specific brain regions, including the striatum and other sites known to express dynorphin and k-receptors (Berridge and Whishaw, 1992;Unterwald et al, 1994;Kalueff et al, 2016).…”