Anxiety-like behavior in mice lacking the angiotensin II type-2 receptor

Abstract

The main biological role of angiotensin II type 2 receptor (AT 2) has not been established. We made use of targeted disruption of the mouse AT 2 gene to examine the role of the AT 2 receptor in the central nervous system (CNS). AT 2-deficient mice displayed anxiety-like behavior compared with wild-type mice. However, AT 2-deficient mice showed no depressant-like activity and no change in hexobarbital-induced sleeping time as compared with findings in wild-type mice. Both noradrenergic and corticotropin-releasing factor (CRF) neuronal systems appear to be involved in this anxiety-like behavior. Diazepam, captopril (angiotensin I converting enzyme inhibitor), prazosin (α 1 antagonist) reversed the anxiety-like behavior in these AT 2-deficient mice, whereas yohimbine (α 2 antagonist), phenylephrine (α 1 agonist), clonidine (α 2 agonist), isoproterenol (β 1/β 2 agonist), propranolol (β 1/β 2 antagonist) and α-helical CRF 9-41 (CRF receptor antagonist) has no apparent effects on anxiety-like behavior in AT 2-deficient mice. In addition, concentrations of plasma adrenocorticotropic hormone (ACTH) and corticosterone in AT 2-deficient mice did not differ from these in wild-type mice, hence, there are probably no endocrine abnormalities involving the hypothalamic-pituitary-adrenal axis (HPA). The amygdala appears to play an important role in many of the responses to fear and anxiety. The number of [ 3 H ]prazosin but not [ 125 I ]CRF binding sites in the amygdala was significantly reduced in AT 2-deficient mice. These findings indicate that the noradrenergic system is involved in mediating the anxiety-like behavior in AT 2-deficient mice.