A Novel Mouse Model of the Glucocorticoid Withdrawal Syndrome

Glucocorticoid withdrawal syndrome (GWS) is increasingly recognized as a major barrier to discontinuing chronic glucocorticoid treatment. Despite high rates of adverse effects, 1% to 3% of the population continues long-term glucocorticoid use, in part due to this poorly understood syndrome. Prominent manifestations of GWS include generalized pain, asthenia, and decreased behavioral motivation, which are only reversed by resuming or increasing glucocorticoid use. Here, we present the first mouse model of GWS designed to investigate its underlying mechanisms, which are so far unknown. Male and female mice were administered chronic high-dose prednisolone via drinking water, followed by withdrawal to low levels. During withdrawal, male and female mice showed an increase in nociceptive behavior in the von Frey test. Female mice also showed decreased interaction with a novel conspecific, despite no change in classic affective behaviors, suggesting a sex-specific decrease in social motivation. We assessed brain glucocorticoid receptor (GR) expression via immunohistochemistry in brain regions involved in pain sensitivity and motivated behavior and found decreased optical density of GR immunoreactivity during chronic prednisolone treatment, specifically in the anterior cingulate cortex. In conclusion, we found that mice exhibit behavioral changes during glucocorticoid withdrawal that mimic the human GWS. This model can therefore be used to study the neural mechanisms of this poorly understood syndrome, including the role of region-specific changes in GR expression.