Adrian J. Dunn

Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses?

The cerebral distribution of CRF and binding sites for CRF ........................................................................................ 2.1. The cerebral distribution of CRF ...................................................................................................................... 2.2. The cerebral distribution of binding sites for CRF ...............................................................................................

Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms

Cancers and cancer treatments produce multiple symptoms that collectively cause a symptom burden for patients. These symptoms include pain, wasting, fatigue, cognitive impairment, anxiety, and depression, many of which co‐occur. There is growing recognition that at least some of these symptoms may share common biologic mechanisms.

Cytokines as mediators of depression: What can we learn from animal studies?

It has recently been postulated that cytokines may cause depressive illness in man. This hypothesis is based on the following observations: 1. Treatment of patients with cytokines can produce symptoms of depression; 2. Activation of the immune system is observed in many depressed patients; 3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction; 4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with antidepressants has been shown to inhibit sickness behavior induced by LPS; 5. Several cytokines can activate the hypothalamo-pituitary-adrenocortical axis (HPAA), which is commonly activated in depressed patients; 6. Some cytokines activates cerebral noradrenergic systems, also commonly observed in depressed patients; 7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment. The evidence for each of these tenets is reviewed and evaluated along with the effects of cytokines in classical animal tests of depression. Although certain sickness behaviors resemble the symptoms of depression, they are not identical and each has distinct features. Thus the value of sickness behavior as an animal model of major depressive disorder is limited, so that care should be taken in extrapolating results from the model to the human disorder. Nevertheless, the model may provide insight into the etiology and the mechanisms underlying some symptoms of major depressive disorder. It is concluded that immune activation and cytokines may be involved in depressive symptoms in some patients. However, cytokines do not appear to be essential mediators of depressive illness.

Systematic interleukin-1 administration stimulates hypothalamic norepinephrine metabolism parallelling the increased plasma corticosterone

Intraperitoneal injection of purified recombinant interleukin-1 (IL-1) into mice increased the cerebral concentration of the norepinephrine (NE) catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), probably reflecting increased activity of noradrenergic neurons. This effect was dose-dependent and was largest in the hypothalamus, especially the medial division. Tryptophan concentrations were also increased throughout the brain. The increase of MHPG peaked around 4 hours after IL-1 administration, parallelling the increase of plasma corticosterone. Both the alpha- and beta-forms of IL-1 were effective, but the activity was lost after heat treatment of the IL-1. Noradrenergic neurons with terminals in the hypothalamus are known to regulate the secretion of corticotropin-releasing factor, thus our results suggest that IL-1 activates the hypothalamic-pituitary-adrenal axis by activating these neurons. Because initiation of an immune response is known to cause systemic release of IL-1, IL-1 may be an immunotransmitter communicating the immunologic activation to the brain. The IL-1-induced changes in hypothalamic MHPG may explain the increases of electrophysiological activity, the changes of hypothalamic NE metabolism, and the increases in circulating glucocorticoids previously reported to be associated with immunologic activation and frequently observed in infected animals.

Effects of Cytokines on Cerebral Neurotransmission

Stress is normally associated with coactivation of the sympathoadrenal system (sympathetic nervous system plus the adrenal medulla) and the hypothalamo-pituitary-adrenocortical (HPA) axis. However, extensive work in the past 30 years has indicated that responses also occur in the central nervous system. The major response occurs in noradrenergic (NA) neurons. Most studies have also noted responses in dopaminergic (DA) and serotonergic (5-HT) systems (Dunn & Kramarcy, 1984; Stone, 1975). Whether or not adrenergic (adrenaline-containing) neurons respond is not resolved, although there is evidence that adrenergic neurons (along with NA and 5-HT neurons) are involved in the regulation of hypothalamic corticotropin-releasing factor (CRF) secretion which initiates HPA activation (Plotsky, Cunningham, & Widmaier, 1989). The NA response is widespread and appears to affect to similar extents both the locus coeruleus (A6) system innervating the dorsal structures (cortex, hippocampus, cerebellum, etc.), and the nucleus tractus solitarius (A1/A2) system innervating the ventral structures (e.g., the hypothalamus). The DA response is also widespread with all the major neuronal systems (nigrostriatal, mesolimbic, mesocortical) showing responses, but the magnitude of the response is particularly large in the mesocortical system (i.e. in the prefrontal and cingulate cortices). The 5-HT response is not markedly regionally specific (although some (e.g., Kirby, Allen, & Lucki, 1995) have reported regional differences). There is also a robust elevation of concentrations of tryptophan (the natural precursor of 5-HT) in all regions of the brain.

Effects of cytokines and infections on brain neurochemistry.

Administration of cytokines to animals can elicit many effects on the brain, particularly neuroendocrine and behavioral effects. Cytokine administration also alters neurotransmission, which may underlie these effects. The most well studied effect is the activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, especially that by interleukin-1 (IL-1). Peripheral and central administration of IL-1 also induces norepinephrine (NE) release in the brain, most markedly in the hypothalamus. Small changes in brain dopamine (DA) are occasionally observed, but these effects are not regionally selective. IL-1 also increases brain concentrations of tryptophan, and the metabolism of serotonin (5-HT) throughout the brain in a regionally nonselective manner. Increases of tryptophan and 5-HT, but not NE, are also elicited by IL-6, which also activates the HPA axis, although it is much less potent in these respects than IL-1. IL-2 has modest effects on DA, NE and 5-HT. Like IL-6, tumor necrosis factor-α (TNFα) activates the HPA axis, but affects NE and tryptophan only at high doses. The interferons (IFNs) induce fever and HPA axis activation in man, but such effects are weak or absent in rodents. The reported effects of IFNs on brain catecholamines and serotonin have been very varied. However, interferon-γ, and to a lesser extent, interferon-α, have profound effects on the catabolism of tryptophan, effectively reducing its concentration in plasma, and may thus limit brain 5-HT synthesis.Administration of endotoxin (LPS) elicits responses similar to those of IL-1. Bacterial and viral infections induce HPA activation, and also increase brain NE and 5-HT metabolism and brain tryptophan. Typically, there is also behavioral depression. These effects are strikingly similar to those of IL-1, suggesting that IL-1 secretion, which accompanies many infections, may mediate these responses. Studies with IL-1 antagonists, support this possibility, although in most cases the antagonism is incomplete, suggesting the existence of multiple mechanisms. Because LPS is known to stimulate the secretion of IL-1, IL-6 and TNFα, it seems likely that these cytokines mediate at least some of the responses, but studies with antagonists indicate that there are multiple mechanisms. The neurochemical responses to cytokines are likely to underlie the endocrine and behavioral responses. The NE response to IL-1 appears to be instrumental in the HPA activation, but other mechanisms exist. Neither the noradrenergic nor the serotonergic systems appear to be involved in the major behavioral responses. The significance of the serotonin response is unknown.

Cytokine Activation of the HPA Axis

Abstract: The observation that administration of interleukin‐1 (IL‐1) to animals activates the hypothalamo‐pituitary‐adrenocortical (HPA) axis stimulated great interest in the significance and mechanism of this response, and in whether other cytokines have similar activities. Interleukin‐6 (IL‐6) and tumor necrosis factor α (TNFα) share HPA‐activating activity, although they are less potent and effective than IL‐1, whereas IL‐2 and interferon α(IFNα) lack activity. Small increases in body temperature occur in response to IL‐1, IL‐6 and TNFα, but these changes are prevented by inhibitors of cyclooxygenase (COX) and do not appear to be related to the HPA‐activation. The rapid HPA‐activating effects of IL‐1 are impaired by COX inhibitors, but the more prolonged HPA activation associated with intraperitoneal injections is not affected, indicating multiple mechanisms for IL‐1‐induced HPA activation. The HPA response to IL‐6 is not sensitive to COX inhibitors, but that to TNFα appears to be. The HPA‐activating activity of IL‐1 is associated with increases in the apparent release of brain noradrenaline (NA) and serotonin (5‐HT), but not dopamine, as well as with increased brain tryptophan. The NA changes, but not those in serotonin metabolism and tryptophan, are prevented by COX inhibitors. IL‐6 has effects on serotonin and tryptophan like those of IL‐1, but no detected effect on NA. TNFα has some effect on NA and tryptophan, but only at relatively high doses. IFNα lacks activity on these neurochemicals. Manipulation of noradrenergic, but not serotonergic systems alters the IL‐1‐induced HPA activation, suggesting the involvement of NA. However, brain NA does not appear to be essential for HPA activation in mice.

Corticotropin-releasing factor has an anxiogenic action in the social interaction test

The effects of intracerebroventricular (icv) injections of corticotropin-releasing factor (CRF, 100 and 300 ng) were investigated in the social interaction test of anxiety in rats. Both doses of CRF significantly decreased active social interaction without a concomitant decrease in locomotor activity. CRF also significantly increased self-grooming, an effect that was independent of the decrease in social interaction. These results indicate an anxiogenic action for CRF. Chlordiazepoxide (CDP, 5 mg/kg ip) pretreatment reversed the anxiogenic effects of icv CRF (100 ng), but CRF did not prevent the sedative effects of CDP. There were no statistically significant changes due to CRF in locomotor activity or rears or head dipping in the holeboard test. Both doses of CRF significantly increased plasma concentrations of corticosterone. The possible mechanisms of the behavioral effects of CRF are discussed.

A cytokine-based neuroimmunologic mechanism of cancer-related symptoms.

While many of the multiple symptoms that cancer patients have are due to the disease, it is increasingly recognized that pain, fatigue, sleep disturbance, cognitive dysfunction and affective symptoms are treatment related, and may lead to treatment delays or premature treatment termination. This symptom burden, a subjective counterpart of tumor burden, causes significant distress. Progress in understanding the mechanisms that underlie these symptoms may lead to new therapies for symptom control. Recently, some of these symptoms have been related to the actions of certain cytokines that produce a constellation of symptoms and behavioral signs when given exogenously to both humans and animals. The cytokine-induced sickness behavior that occurs in animals after the administration of infectious or inflammatory agents or certain proinflammatory cytokines has much in common with the symptoms experienced by cancer patients. Accordingly, we propose that cancer-related symptom clusters share common cytokine-based neuroimmunologic mechanisms. In this review, we provide evidence from clinical and animal studies that correlate the altered cytokine profile with cancer-related symptoms. We also propose that the expression of coexisting symptoms is linked to the deregulated activity of nuclear factor-kappa B, the transcription factor responsible for the production of cytokines and mediators of the inflammatory responses due to cancer and/or cancer treatment. These concepts open exciting new avenues for translational research in the pathophysiology and treatment of cancer-related symptoms.

Corticotropin-releasing factor administration elicits a stress-like activation of cerebral catecholaminergic systems

The cerebral content of the biogenic amines, dopamine (DA), norepinephrine (NE), and serotonin (5-HT) and their catabolites 30 min after CRF or saline injections was determined using HPLC with electrochemical detection. Injection of CRF (1.0 micrograms) into the lateral ventricles (ICV) of mice produced a behavioral activation in which their motor movements appeared as bursts of activity followed by periods of immobility. CRF administration (ICV or SC) did not alter the concentrations of DA, NE, tryptophan, 5-HT, or 5-hydroxyindoleacetic acid (5-HIAA) in any brain region measured. ICV CRF increased the concentrations of dihydroxyphenylacetic acid (DOPAC), the major catabolite of DA, and of 3-methoxy,4-hydroxyphenylethyleneglycol (MHPG), the major catabolite of NE, in several brain regions. DOPAC:DA ratios were consistently increased in prefrontal cortex, septum, hypothalamus, and brain stem relative to animals injected with saline. MHPG:NE ratios were also increased in the prefrontal cortex and hypothalamus, with a marginal effect (p = 0.06) in brain stem. SC CRF significantly increased DOPAC:DA in prefrontal cortex, and MHPG:NE in prefrontal cortex, hypothalamus and brain stem. Pretreatment with naloxone did not prevent any of the neurochemical responses to ICV CRF, but naloxone alone increased DOPAC:DA in medial profrontal cortex, and decreased MHPG:NE in nucleus accumbens in CRF-injected mice. These results suggest that administration of CRF either centrally or peripherally induces an activation of both dopaminergic and noradrenergic systems in several regions of mouse brain.(ABSTRACT TRUNCATED AT 250 WORDS)