Glucocorticoids are released after hypothalamus-pituitary-adrenal axis stimulation by stress and act both in the periphery and in the brain to bring about adaptive responses that are essential for life. Dysregulation of the stress response can precipitate
psychiatric diseases, in particular depression. Recent genetic studies have suggested that the
glucocorticoid carrier
transcortin, also called
corticosteroid-binding globulin (
CBG), may have an important role in stress response. We have investigated the effect of partial or total
transcortin deficiency using
transcortin knockout mice on hypothalamus-pituitary-adrenal axis functioning and regulation as well as on behaviors linked to anxiety and depression traits in animals. We show that
CBG deficiency in mice results in markedly reduced total circulating
corticosterone at rest and in response to stress. Interestingly, free
corticosterone concentrations are normal at rest but present a reduced surge after stress in
transcortin-deficient mice. No differences were detected between
transcortin-deficient mice for anxiety-related traits. However,
transcortin-deficient mice display increased immobility in the forced-swimming test and markedly enhanced learned helplessness after prolonged uncontrollable stress. The latter is associated with an approximately 30% decrease in circulating levels of free
corticosterone as well as reduced Egr-1
mRNA expression in hippocampus in
CBG-deficient mice. Additionally,
transcortin-deficient mice show no sensitization to
cocaine-induced locomotor responses, a well described
corticosterone-dependent test. Thus,
transcortin deficiency leads to insufficient
glucocorticoid signaling and altered behavioral responses after stress. These findings uncover the critical role of plasma
transcortin in providing an adequate endocrine and behavioral response to stress.