Antidepressant-like behavioral effects of impaired cannabinoid receptor type 1 signaling coincide with exaggerated corticosterone secretion in mice

Hypothalamic-pituitary-adrenocortical (HPA) axis hyperactivity is associated with major depressive disorders, and treatment with classical antidepressants ameliorates not only psychopathological symptoms, but also the dysregulation of the HPA axis. Here, we further elucidated the role of impaired cannabinoid type 1 receptor (CB1) signaling for neuroendocrine and behavioral stress coping in the mouse forced swim test (FST). We demonstrate that the genetic inactivation of CB1 is accompanied by increased plasma corticosterone levels both under basal conditions and at different time points following exposure to the FST The latter effect could be mimicked in C57BL/6N mice by acute, subchronic, and chronic administration of the selective CB1 antagonist SR141716. Further experiments confirmed the specificity of corticosterone-elevating SR141716 actions for CB1 in CB1-deficient mice. Subchronic and chronic pharmacological blockade of CB1, but not its genetic deletion, induced antidepressant-like behavioral responses in the FST that were characterized by decreased floating and/or increased struggling behavior. The antidepressant-like behavioral effects of acute desipramine treatment in the FST were absent in CB1-deficient mice, but the dampening effects of desipramine on FST stress-induced corticosterone secretion were not compromised by CB1 deficiency. However, antidepressant-like behavioral desipramine effects were intact in C57BL/6N mice pre-treated with SR141716, indicating potential developmental deficits in CB1-deficient mice. We conclude that pharmacological blockade of CB1 signaling shares antidepressant-like behavioral effects with desipramine, but reveals opposite effects on HPA axis activity. (C) 2007 Elsevier Ltd. All rights reserved.