Candesartan reverses depression‐like behavior and negative cardiovascular changes in a rodent model of depression: comparison to the selective serotonin reuptake inhibitor fluoxetine

Depression and cardiovascular disease (CVD) are highly comorbid. Antidepressants may not improve cardiovascular function, even when depressive behavior is improved. Conversely, angiotensin receptor antagonists, which are useful in treating CVD, have been shown to have antidepressant properties. The current study compared the impact of treatment with an AT1 receptor antagonist or the SSRI fluoxetine on behavioral and cardiovascular parameters in a rodent model of depression. Rats selectively bred for low activity in a novel environment were exposed to chronic mild stress (CMS). Anhedonic behavior was assessed via weekly sucrose preference tests (SPT). Heart rate (HR) and HR variability (HRV) were measured by radiotelemetry. CMS reduced SPT and decreased HRV, consistent with early studies on CMS‐induced depression. After 4 weeks of CMS, candesartan (0.5 mg/kg/day; n=8), fluoxetine (4 mg/kg/day; n=8) or vehicle were administered sc by osmotic minipump; CMS was continued for another 4 weeks. Candesartan rapidly improved SPT scores, reduced anxiety‐like behavior, and improved decreased HRV. Fluoxetine also improved anhedonia and anxiety‐like behavior, but not HRV, and reduced HRV in unstressed controls. These results suggest AT1 receptor antagonists may be beneficial for the treatment of comorbid depression and CVD. (HA: N000140210879, NIDA 5P01DA021633; SMC: 1K99MH085859‐01A1; IAK: 1K99MH081927)