Depressive and cardiovascular disease comorbidity in a rat model of social stress: a putative role for corticotropin-releasing factor

Abstract

Rationale Depression is associated with medical comorbidities, particularly cardiovascular disease. However, mechanisms linking depression and cardiovascular disease remain unclear. Objectives This study investigated whether the rat resident–intruder model of social stress would elicit behavioral dysfunctions and autonomic changes characteristic of psychiatric/cardiovascular comorbidity. Furthermore, the efficacy of the corticotropin-releasing factor-1 (CRF1) receptor antagonist, NBI-30775 (NBI), or the tricyclic antidepressant, desipramine (DMI), to prevent social stress-induced behavioral, neuroendocrine, and cardiovascular changes were evaluated. Methods Adult male rats were exposed to resident–intruder stress (seven consecutive days) and systemically administered NBI (10 mg/kg/7 days), DMI (10 mg/kg/14 days), or vehicle. The efficacy of NBI and DMI to alter the behavioral and neuroendocrine responses to social stress was assessed. Furthermore, their effects on stress-induced forced swim behavior (FST), bladder and adrenal weight, and heart rate variability (HRV) were examined. Results NBI, but not DMI, increased time spent in an upright, defensive posture and the latency to submit to the resident. Additionally, only NBI reduced social stress-induced adrenocorticotropic hormone and corticosterone release. Social stress increased FST immobility, caused bladder and adrenal hypertrophy, and decreased HRV. Both NBI and DMI blocked stress-induced increases in immobility during the FST. However, only NBI inhibited social stress-induced adrenal and bladder hypertrophy and decreases in heart rate variability. Conclusions Rat resident–intruder stress paradigm models aspects of psychiatric/medical comorbidity. Furthermore, the CRF system may contribute to both the behavioral response during social stress and its behavioral and autonomic consequences, offering insight into potential therapy to treat these comorbid conditions.

A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats

“…In a recent study of the effects of NBI-30775 on cardiovascular consequences of social stress, the antagonist was demonstrated to prevent stress-induced increases in bladder mass (46). The present study confirmed that finding and further showed that repeated administration of NBI-30775 prevented the urodynamic consequences of repeated social stress.…”

“…B: bar graph indicates the mean number of CRF mRNA-expressing Barrington's nucleus neurons for rats infused with shRNA-CRF scrambled (n ϭ 4) and shRNA-CRF (n ϭ 6). *P Ͻ 0.05. behavioral, cardiovascular, and bladder hypertrophic effects of repeated social defeat stress (46). Systemic NBI-30775 could act at multiple sites.…”

“…This dose of NBI-30775 has a half-life of 130 min in vivo and has been shown to result in 75% occupancy of brain CRF 1 (8,9,11). Additionally, this has been demonstrated to prevent stress-induced ACTH release and behavioral and cardiovascular consequences of social stress (14,46).…”

Adolescent Social Stress Produces an Enduring Activation of the Rat Locus Coeruleus and Alters its Coherence with the Prefrontal Cortex

“…Human social stress is modeled in rodents using the resident-intruder model (Miczek, 1979). Adult male rats repeatedly exposed to resident-intruder stress display endocrine, autonomic and behavioral features that characterize mood disorders in humans, underscoring the potential of this model to produce correlates of stress-related psychiatric diseases Rygula et al, 2005;Wood et al, 2010Wood et al, , 2012Wood et al, , 2013. Although less well studied, adolescent male rats exposed to repeated resident-intruder stress have been reported to have cognitive impairments and escalated cocaine self-administration when tested in adulthood (Burke and Miczek, 2015;Novick et al, 2013;Snyder et al, 2015).…”

Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History

“…CRF-related plasticity in the DRN may be one mechanism for this shift. The finding that this adaptation is most apparent in the LL subpopulation, the population that is relatively resistant to developing depression-related endocrine, behavioral and cardiovascular endpoints suggests links between coping style and the cognitive consequences of stress (Wood et al, 2010(Wood et al, , 2012.…”