The contribution of the locus coeruleus-norepinephrine system in the emergence of defeat-induced inflammatory priming.

Exposure to psychosocial stress is known to precipitate the emergence of stress related psychiatric disorders such as depression and anxiety. While mechanisms by which this occurs remain largely unclear, recent evidence points towards a causative role for inflammation. Neurotransmitters, such as norepinephrine (NE), are capable of regulating expression of proinflammatory cytokines and thus may contribute to the emergence of stress-related disorders. The locus coeruleus (LC) is the major source of norepinephrine (NE) to the brain and therefore the current study utilized N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), an LC selective noradrenergic neurotoxin, to determine the discrete involvement of the LC-NE system in social defeat-induced inflammation in LC projection regions including the central amygdala (CeA), dorsal raphe (DR) and plasma. In the current study, rats were exposed to brief social defeat or control manipulations on 5 consecutive days. To determine whether a history of social defeat enhanced or "primed" the inflammatory response to a subsequent defeat exposure, all rats regardless of stress history were exposed to an acute social defeat challenge immediately preceeding tissue collection. As anticipated, prior history of social defeat primed inflammatory responses in the plasma and CeA while neuroinflammation in the DR was markedly reduced. Notably, DSP-4 treatment suppressed stress-induced circulating inflammatory cytokines independent of prior stress history. In contrast, neuroinflammation in the CeA and DR were greatly augmented selectively in DSP-4 treated rats with a history of social defeat. Together these data highlight the dichotomous nature of NE in stress-induced inflammatory priming in the periphery and the brain and directly implicate the LC-NE system in these processes.

Essential Role of Ovarian Hormones in Susceptibility to the Consequences of Witnessing Social Defeat in Female Rats.

BACKGROUND: Women are at greater risk than men of developing depression and comorbid disorders such as cardiovascular disease. This enhanced risk begins at puberty and ends following menopause, suggesting a role for ovarian hormones in this sensitivity. Here we used a model of psychosocial witness stress in female rats to determine the stress-induced neurobiological adaptations that underlie stress susceptibility in an ovarian hormone-dependent manner. METHODS: Intact or ovariectomized (OVX) female rats were exposed to five daily 15-minute witness-stress exposures. Witness-stress-evoked burying, behavioral despair, and anhedonia were measured. Cardiovascular telemetry was combined with plasma measurements of inflammation, epinephrine, and corticosterone as indices of cardiovascular dysfunction. Finally, levels of interleukin-1ß and corticotropin-releasing factor were assessed in the central amygdala. RESULTS: Witness stress produced anxiety-like burying, depressive-like anhedonia, and behavioral despair selectively in intact female rats, which was associated with enhanced sympathetic responses during stress, including increased blood pressure, heart rate, and arrhythmias. Moreover, intact female rats exhibited increases in 12-hour resting systolic pressure and heart rate and reductions in heart rate variability. Notably, OVX female rats remained resilient. Moreover, intact, but not OVX, female rats exposed to witness stress exhibited a sensitized cytokine and epinephrine response to stress and distinct increases in levels of corticotropin-releasing factor and interleukin-1ß in the central amygdala. CONCLUSIONS: Together these data suggest that ovarian hormones play a critical role in the behavioral, inflammatory, and cardiovascular susceptibility to social stress in female rats and reveal putative systems that are sensitized to stress in an ovarian hormone-dependent manner.

Physical versus psychological social stress in male rats reveals distinct cardiovascular, inflammatory and behavioral consequences.

Repeated exposure to social stress can precipitate the development of psychosocial disorders including depression and comorbid cardiovascular disease. While a major component of social stress often encompasses physical interactions, purely psychological stressors (i.e. witnessing a traumatic event) also fall under the scope of social stress. The current study determined whether the acute stress response and susceptibility to stress-related consequences differed based on whether the stressor consisted of physical versus purely psychological social stress. Using a modified resident-intruder paradigm, male rats were either directly exposed to repeated social defeat stress (intruder) or witnessed a male rat being defeated. Cardiovascular parameters, behavioral anhedonia, and inflammatory cytokines in plasma and the stress-sensitive locus coeruleus were compared between intruder, witness, and control rats. Surprisingly intruders and witnesses exhibited nearly identical increases in mean arterial pressure and heart rate during acute and repeated stress exposures, yet only intruders exhibited stress-induced arrhythmias. Furthermore, re-exposure to the stress environment in the absence of the resident produced robust pressor and tachycardic responses in both stress conditions indicating the robust and enduring nature of social stress. In contrast, the long-term consequences of these stressors were distinct. Intruders were characterized by enhanced inflammatory sensitivity in plasma, while witnesses were characterized by the emergence of depressive-like anhedonia, transient increases in systolic blood pressure and plasma levels of tissue inhibitor of metalloproteinase. The current study highlights that while the acute cardiovascular responses to stress were identical between intruders and witnesses, these stressors produced distinct differences in the enduring consequences to stress, suggesting that witness stress may be more likely to produce long-term cardiovascular dysfunction and comorbid behavioral anhedonia while exposure to physical stressors may bias the system towards sensitivity to inflammatory disorders.