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.

Corticotropin-releasing factor (CRF), the stress-related neuropeptide, acts as a neurotransmitter in the brain norepinephrine nucleus, locus coeruleus (LC), to activate this system during stress. CRF shifts the mode of LC discharge from a phasic to a high tonic state that is thought to promote behavioral flexibility. To investigate this, the effects of CRF administered either intracerebroventricularly (30-300 ng, i.c.v.) or directly into the LC (intra-LC; 2-20 ng) were examined in a rat model of attentional set shifting. CRF differentially affected components of the task depending on dose and route of administration. Intracerebroventricular CRF impaired intradimensional set shifting, reversal learning, and extradimensional set shifting (EDS) at different doses. In contrast, intra-LC CRF did not impair any aspect of the task. The highest dose of CRF (20 ng) facilitated reversal learning and the lowest dose (2 ng) improved EDS. The dose-response relationship for CRF on EDS performance resembled an inverted U-shaped curve with the highest dose having no effect. Intra-LC CRF also elicited c-fos expression in prefrontal cortical neurons with an inverted U-shaped dose-response relationship. The number of c-fos profiles was positively correlated with EDS performance. Given that CRF excites LC neurons, the ability of intra-LC CRF to activate prefrontal cortical neurons and facilitate EDS is consistent with findings implicating LC-norepinephrine projections to medial prefrontal cortex in this process. Importantly, the results suggest that CRF release in the LC during stress facilitates shifting of attention between diverse stimuli in a dynamic environment so that the organism can adapt an optimal strategy for coping with the challenge.

Many neural programs that shape behavior become established during adolescence. Adverse events at this age can have enduring consequences for both adolescent and adult mental health. Here we show that repeated social stress at different stages of adolescent development differentially affects rat behavior and neuronal activity. Early-adolescent (PND 28, EA), mid-adolescent (PND 42, MA), and adult (PND 63) rats were subjected to resident-intruder social stress (7 days) and behavior was examined 24-72 h later. In EA rats selectively, resident-intruder stress increased proactive responses in the defensive burying and forced swim tests. In adult rats, resident-intruder stress decreased burying behavior regardless of whether the animal was stressed as an adult or during early adolescence. Because the locus coeruleus (LC)-norepinephrine system has been implicated in proactive defense behaviors, LC neuronal activity was quantified in separate cohorts. Stressed EA rats had elevated spontaneous LC discharge rates and diminished responses to sensory stimuli compared to controls. Microinjection of a CRF antagonist into the LC selectively inhibited neurons of stressed EA rats, suggesting that EA social stress induces tonic CRF release onto LC neurons, shifting the mode of discharge to an activated state that promotes active defensive behaviors. In all adult groups, resident-intruder stress resulted in an increased phasic response to sensory stimuli with no change in spontaneous rates. Mid-adolescence was a transition period during which social stress did not affect behavior or LC activity. The results suggest that social stress interacts with the brain norepinephrine system to regulate defensive strategies in an age-dependent manner.

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Wood SK, McFadden K, Griffin T, Wolfe JH, Zderic S, Valentino RJ. A corticotropin-releasing factor receptor antagonist improves urodynamic dysfunction produced by social stress or partial bladder outlet obstruction in male rats. Am J Physiol Regul Integr Comp Physiol 304: R940 -R950, 2013. First published April 3, 2013 doi:10.1152/ajpregu.00257.2012.-Barrington's nucleus, in the pons, regulates micturition through spinal projections to preganglionic parasympathetic neurons. The stress neuropeptide CRF is prominent in these projections and has an inhibitory influence. Social stress in rats causes urinary retention and abnormal urodynamics resembling those produced by partial bladder outlet obstruction (pBOO), and this is associated with CRF upregulation in Barrington's nucleus. Here, we examined the role of CRF in social stress-and pBOO-induced urodynamic dysfunction by assessing the ability of a CRF 1 receptor antagonist to alter these effects. Male rats exposed to repeated resident-intruder stress were administered vehicle or a CRF1 antagonist (NBI-30775) daily prior to the stress. Urodynamic function was recorded in the unanesthetized state 72 h after the final stress. NBI-30775 prevented the increased intermicturition interval, micturition volume, and bladder capacity produced by social stress, but not the increase in CRF expression in Barrington's nucleus neurons. The urinary dysfunction was also partly prevented by shRNA targeting of CRF in Barrington's nucleus, suggesting that stress-induced urinary dysfunction results, in part, from CRF upregulation in Barrington's nucleus and enhanced postsynaptic effects in the spinal cord. Finally, NBI-30775 improved urodynamic function of rats that had pBOO of 2-wk duration when administered daily during the second week but did not block the increase in CRF expression in Barrington's nucleus neurons. These findings implicate a role for Barrington's nucleus CRF in stress-and pBOO-induced urodynamic changes and suggest that CRF1 antagonists may be useful therapeutic agents for the treatment of urinary dysfunction. cystometry; resident-intruder; Barrington's nucleus; urinary BARRINGTON'S NUCLEUS IN THE pons regulates the descending limb of the micturition reflex through its axonal projections to preganglionic neurons of the lumbosacral spinal cord that provide the parasympathetic input to the detrusor muscle (21). Electrical and chemical stimulation of Barrington's nucleus elicits detrusor contraction, and conversely, lesions disrupt the micturition reflex (1,27,29). More recent anatomical and physiological evidence suggests that Barrington's nucleus plays a key role in coordinating central and visceral responses during micturition (39) (for review, see Ref. 41). In addition to its connections to the bladder, Barrington's nucleus neurons are transsynaptically linked to the distal colon and other pelvic viscera, suggesting a broader role for this nucleus in the regulation of pelvic visceral functions (23,24,33,40,44). Elucidating the function of neuromodulators expresse...

The stress-related neuropeptide, corticotropin-releasing factor (CRF), is prominent in neurons of the pontine micturition center, Barrington’s nucleus. These neurons co-innervate spinal preganglionic neurons that control the bladder and locus coeruleus (LC) neurons that provide norepinephrine innervation throughout the brain. Adeno-associated viral (AAV) vector-mediated transfer of CRF cDNA was used to increase CRF expression in Barrington’s nucleus neurons and investigate the impact of a gain of function in Barrington’s nucleus spinal and LC projections. AAV transfer of the reverse CRF cDNA sequence served as the control. Bladder urodynamics and behavior were assessed four weeks after vector injection into Barrington’s nucleus. Rats with bilateral injections of AAV-CRF cDNA into Barrington’s nucleus had immunohistochemical evidence of CRF overexpression in neurons and transport to the spinal cord and LC. The bladder: body weight ratio was greater and micturition pressure was less in these rats compared to controls, consistent with an inhibitory influence on bladder function. Other indices of urodynamic function were not altered. CRF innervation of the LC was increased in rats with bilateral Barrington’s nucleus injections of AAV-CRF cDNA and this was associated with increased burying behavior, an endpoint of LC activation by CRF. The results provide immunohistochemical evidence for viral vector-induced CRF overexpression in Barrington’s nucleus neurons and underscore the ability of AAV vector-mediated transfer to increase CRF function in selective circuits. The findings support an inhibitory influence of CRF in Barrington’s nucleus regulation of the bladder and an excitatory influence on the brain norepinephrine system that translates to behavioral activation.

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The research goal was to determine whether social stress differentially impacts on behavior and brain physiology during critical windows in adolescent development. Early adolescent (EA), mid‐adolescent (MA) and adult rats were exposed to 7 days of a social stressor, the resident‐intruder paradigm. Social stress had divergent effects on behavior in EA and adult rats, promoting active coping behaviors in EA rats and decreasing active coping behaviors in adult rats as determined by the defensive burying test and response to swim stress. Mid‐adolescent rats exposed to social stress showed no changes in the behavioral endpoints. Effects of social stress in EA rats was not mimicked by chronic restraint stress. Because the locus coeruleus (LC)‐norepinephrine system has been implicated in certain active coping behaviors, LC neuronal activity was recorded in EA rats exposed to social stress and matched controls. LC spontaneous firing rates were higher in EA rats exposed to social stress. Moreover, intra‐LC infusion of the CRF antagonist, DPheCRF12‐41, inhibited LC neurons of stressed rats but not controls. These data suggest that exposure to social stress in early adolescence promotes tonic secretion of CRF into the LC to activate this system. This CRF‐induced activation of the LC‐norepinephrine system may underlie the promotion of active‐coping behaviors noted in socially stressed EA rats.MH058250