Cytokines as a stressor: Implications for depressive illness

Stressful events have been implicated in the provocation of depressive illness. Inasmuch as immunological challenge, and particularly cytokine administration, engender neuroendocrine and central neurochemical changes reminiscent of those provoked by psychogenic stressors, it was suggested that immune activation may also contribute to affective illness. The present report provides a brief overview of the neurochemical sequelae of acute and repeated interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α) and IL-2 treatment, describes some of the synergisms associated with these treatments, as well as their potential interactions with psychogenic stressors. In addition, a discussion is provided concerning the fact that cytokines, like stressors, may have time-dependent proactive effects, so that re-exposure to the treatments provoke greatly augmented neurochemical changes (sensitization). Given that the effects of cytokines are evident within hypothalamic, as well as extrahypothalamic sites, including various limbic regions, it is suggested that cytokines may impact on emotional changes, including depression

Learned helplessness in mice

Exposure to inescapable shock provokes behavioral disturbances in subsequent shock-escape tests, as well as in other behavioral paradigms, including those that reflect anhedonia. The interference induced by inescapable shock using a yoked (triadic) paradigm has frequently been referred to as a "learned helplessness" paradigm. The interference effect, although attributed to cognitive factors by several investigators, has also been explained on the basis of neurochemical changes induced by the uncontrollable stressor. In the present report, we briefly describe the various theoretical positions concerning the interference effect induced by inescapable hock, describe procedures that can be used to investigate this phenomenon in mice, and provide caveats that might be considered in conducting these experiments

Stress and cytokine-elicited neuroendocrine and neurotransmitter sensitization: Implications for depressive illness

Stressful events, by their effects on neurotransmitter and neuroendocrine processes, are thought to favor the development or exacerbation of depressive illness. In as much as immunological challenge, may provoke stressor-like neuroendocrine and central neurochemical changes, the view was offered that immune activation essentially acts like a stressor and may contribute to the evolution of affective illness. In this respect, viral and bacterial infections appear to influence behavioral/metabolic (e.g. fever, anorexia, somnolence) and neurotransmitter functioning through the release of cytokines, which act as messengers between the immune system and brain. The present report provides a brief overview of the neurochemical consequences of proinflammatory cytokine treatments, particularly the actions of interleukin (IL)-1β and tumor necrosis factor-α. As well, synergy with psychogenic and neurogenic stressors are described, as are data showing that cytokines, like stressors, may have timedependent proactive (sensitization) effects, so that reexposure to the treatments greatly augments hypothalamic-pituitary-adrenal activity, as well as central neurochemical changes. Indeed, the neurotransmitter alterations are not restricted to hypothalamic nuclei, but occur in several extrahypothalamic sites, including various limbic regions. It is suggested that by virtue of these neurochemical changes, cytokines may have both immediate and proactive effects on mood states

Further evidence for the depressive effects of cytokines: Anhedonia and neurochemical changes

Although human studies have emphasized a role for IL-2 in depressive illness, limited attention has been devoted to the behavioral and neurochemical effects of this cytokine in animal studies. The present review assesses the behavioral effects of IL-2 in rodents, in counterpoint to the effects of interleukin-1β (IL-1β), necrosis factor-α (TNF-α) and endotoxin challenge. Unlike IL-1β, systemic IL-2 provokes modest effects on hypothalamic-pituitary–adrenal (HPA) functioning, and does not provoke marked signs of illness or anxiety. In some respects, however, IL-2 elicits effects reminiscent of traditional stressors, including anhedonia (diminished pleasure gained from otherwise rewarding stimuli). Additionally, when chronically administered, IL-2 may impact on cognitive processes, including spatial working memory. While IL-2 may induce depressive-like symptoms, the available data are sparse, have hardly considered the impact of chronic cytokine treatment, only assessed behavior in a narrow range of tests, and it remains to be established whether the effects of IL-2 are modifiable by antidepressant treatments. Finally, as the effects of IL-2 on CNS processes vary in a biphasic fashion, and may also engender neurotoxic effects, further analyses are necessary to discern under what conditions this cytokine provokes depressive-like behavioral outcomes

Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice

Although numerous behavioral tests are available to assess anxiety, we introduce a simplified version of a previously established test that is exquisitely sensitive and reliable. The latency to consume a palatable snack (graham wafer crumbs) was assessed among mice in their home cage and in an unfamiliar environment, as well as in the presence or absence of predator scent. The effects of various anxiolytics and nonanxiolytics were evaluated in these paradigms. When offered the palatable snack in a familiar environment, mice readily approached and began consumption; however, in a novel environment (cage with fresh bedding), or in the presence of predator scent (rat feces), response latencies increased 10-fold. Anxiolytics, including diazepam, chlordiazepoxide, propranolol, or chronic treatment with either buspirone or the antidepressant desmethylimipramine attenuated the effects in the novel environment without affecting home-cage responding. In contrast, nonanxiolytic agents (haloperidol, amphetamine, acute buspirone or desmethylimipramine) failed to exclusively affect novel environment-induced prolongation of response latencies. The simplicity of design, the absence of food deprivation or neurogenic stressors, the possibility of using it in a repeated measures design, the reliability and magnitude of response, and the specificity and sensitivity to anxiolytic drugs makes this an ideal preparation with which to assess anxiety and anxiety-altering manipulations

Dissociating anorexia and anhedonia elicited by interleukin-1β: Antidepressant and gender effects on responding for "free chow" and "earned" sucrose intake

Rationale: Cytokines, signaling molecules of the immune system, have been implicated in the provocation of depression. Analysis of the behavioral effects of interleukin-1beta (IL-1beta), and their modification by antidepressants, is complicated since the anorexic and anhedonic effects of the cytokine are not readily dissociated from one another. Objectives: The effects of IL-1beta in male and female rats were evaluated with respect to free consumption of lab chow and responding for sucrose reward on a progressive ratio (PR) schedule. This schedule assesses motivation to respond by progressively increasing the efforts rats must expend to receive a fixed reward. Using this schedule, it was then possible to assess the influence of chronic fluoxetine in attenuating the effects of IL-1beta. Methods: The effect of a single intraperitoneal injection of IL-1beta treatment was assessed in rats trained to respond on a PR schedule for sucrose reward, and who could obtain ad lib chow. In a second experiment rats were pretreated chronically with fluoxetine by gavage for 30 days, after which the effects of IL-1beta were assessed. Results: A single intraperitoneal injection of IL-1beta reduced chow consumption for 48 h in both males and females; in contrast, among males, the effort expended to gain sucrose reward was reduced for 24 h, while in females the effect persisted for 72 h. Chronic pretreatment with fluoxetine attenuated the disturbance of PR performance elicited by IL-1beta, but did not alter the reduced chow consumption. Conclusions: It is suggested that (a). the anhedonic and anorexic effects of IL-1beta are dissociable, (b). the cytokine disturbs incentive motivation, and (c). antidepressant treatment preferentially influences the anhedonic effects elicited by IL-1beta

Influence of Psychogenic and Neurogenic Stressors on Endocrine and Immune Activity: Differential Effects in Fast and Slow Seizing Rat Strains

Variations of plasma ACTH and corticosterone, as well as splenic macrophage activity and mitogen-induced cell proliferation, were determined in rats following 15 min of either the neurogenic stressor of restraint or by a purely psychogenic stressor consisting of exposure to a ferret. The effects of these stressors were assessed in two strains of rats that were selectively bred for either Fast or Slow kindling epileptogenesis triggered in response to amygdala stimulation. The stressors differentially influenced behavioral responses, endocrine activity, and immune functioning, and these effects varied with the strain of rat. In response to restraint the Fast rats exhibited protracted struggling, while the Slow rats tended to be immobile. In contrast, upon ferret exposure the Fast rats showed greater immobility than the Slow rats. The stressors also induced marked elevations of plasma ACTH and corticosterone. Whereas the ACTH and corticosterone increases were more pronounced in response to the ferret in the Slow rats, restraint resulted in a markedly greater rise of plasma ACTH in the Fast strain. Proliferation of splenic lymphocytes in response to Con A and LPS were elevated in Fast seizing rats, while macrophage activity, as determined by oxygen burst following addition of PMA and luminol to splenic mononuclear cells, was greater in the Slow seizing strain. While neither stressor influenced cell proliferation in either the Fast or Slow rats, macrophage activity was greatly suppressed by ferret exposure only in the Slow rats. Taken together, it appears that while stressors influence behavior and immune and endocrine functioning, these effects may vary as a function of the interaction of the strain of rat and the specific type of stressor employed