Abstract
Various disturbances of social behavior, such as autism, depression, or posttraumatic stress disorder, have been associated with an altered steroid hormone homeostasis and a dysregulation of the hypothalamus–pituitary–adrenal axis. A link between steroid hormone antagonists and the treatment of stress-related conditions has been suggested. We evaluated the effects of stress induction on social behavior in the three chambers and its potential reversibility upon specific steroid hormone antagonism in mice. C57BL/6 mice were stressed twice daily for 8 days by chronic swim testing. Social behavior was evaluated by measuring, first, the preference for sociability and, second, the preference for social novelty in the three-chamber approach before and after the chronic swim test. The reversibility of behavior upon stress induction was analyzed after applying steroid hormone antagonists targeting glucocorticoids with etomidate, mineralocorticoids with potassium canrenoate, and androgens with cyproterone acetate and metformin. In the chronic swim test, increased floating time from 0.8 ± 0.2 min up to 4.8 ± 0.25 min was detected (p < 0.01). In the three-chamber approach, increased preference for sociability and decreased preference for social novelty was detected pre- versus post-stress induction. These alterations of social behavior were barely affected by etomidate and potassium canrenoate, whereas the two androgen antagonists metformin and cyproterone acetate restored social behavior even beyond baseline conditions. The alteration of social behavior was better reversed by the androgen as compared with the glucocorticoid and mineralocorticoid antagonists. This suggests that social behavior is primarily controlled by androgen rather than by glucocorticoid or mineralocorticoid action. The stress-induced changes in preference for sociability are incompletely explained by steroid hormone action alone. As the best response was related to metformin, an effect via glucose levels might confound the results and should be subject to future research.
Highlights
Long disturbances of social behavior, such as autism, depression, or posttraumatic stress disorder (PTSD), have been associated with an altered steroid homeostasis and a dysregulation of the hypothalamus–pituitary–adrenal axis (HPA) (Bondar et al 2018; Jacobson 2014; Du and Pang 2015; Sriram et al 2012)
Autistic disorders have been associated with HPA dysregulation (Brosnan et al 2009; Marinović-Curin et al 2008; Hoshino et al 1987), given differences of the anatomic structure of the hypothalamus (Bitsika et al 2014; Hollocks et al 2014), of the pituitary gland (Brosnan et al 2009; Hamza et al 2010; Curin et al 2003; Iwata et al 2011; Xu et al 2015), and of the adrenal gland (Curin et al 2003; Baron-Cohen et al 2015; El-Baz et al 2014; Taylor and Corbett 2014; Ruta et al 2011; Ingudomnukul et al 2007; Majewska et al 2014; Takagishi et al 2010; Chakrabarti et al 2009; Knickmeyer et al 2006)
We could clearly establish the impact of induced stress using the forced swimming model on social behavior with an increase of the preference for sociability and a decrease in the preference of social novelty
Summary
Long disturbances of social behavior, such as autism, depression, or posttraumatic stress disorder (PTSD), have been associated with an altered steroid homeostasis and a dysregulation of the hypothalamus–pituitary–adrenal axis (HPA) (Bondar et al 2018; Jacobson 2014; Du and Pang 2015; Sriram et al 2012). Chronic stress is generally characterized by a strong stimulation of the central drive combined with a downregulation of its negative feedback upon increased steroid hormone availability; similar processes are associated with depression (Checkley 1996). Steroid hormones allow to regulate behavior in response to sudden and short-lived environmental or social change serving as intermediators (Steinman and Trainor 2010; Ayash et al 2019)
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